Unusual Amino Acids in Medicinal Chemistry - Journal of Medicinal

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Unusual Amino Acids in Medicinal Chemistry Mark Arnold Thomas Blaskovich J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b00319 • Publication Date (Web): 02 Sep 2016 Downloaded from http://pubs.acs.org on September 3, 2016

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Journal of Medicinal Chemistry

Unusual Amino Acids in Medicinal Chemistry Mark A. T. Blaskovich* Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia 4072

ABSTRACT: Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalised amine and carboxyl groups attached to a chiral center group along with one or two potentially diverse side chains provides a unique three-dimensional structure with high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs on their own. This perspective highlights the diversity of unnatural amino acid structures found in hit-tolead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

1. INTRODUCTION Amino Acids. Amino acids are have played a significant role in drugs from the earliest days of modern drug discovery, contained in natural products such as the antibiotics bacitracin and vancomycin and in peptides such as insulin. They are indispensable components of ACS Paragon Plus Environment


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modern medicinal chemistry and are becoming increasingly prominent in new drugs due to three growing trends, the desire to ‘escape from flatland’1 the growing acceptance of peptides and modified peptides as drugs,2,3 and the increasing commercial availability and ease of synthesis of a wide range of amino acids with diverse side chains. No other readily available building block contains two orthogonal functional groups that are able to be modified by convenient chemistry such as acylation, alkylation and amidation, with one or two additional diversity elements (also potentially derivatisable) directly attached to the same chiral center, presenting all components in a compact chiral configuration. While most chemists are aware of the 20 standard ‘proteinogenic’ amino acids (a term generally applied to the 20 primary amino acids most commonly found in proteins), they may not be aware that the genetically encoded list of amino acids also includes two more amino acids, selenocysteine 14 and pyrrolysine 25 (Scheme 1). The “proteinogenic” classification is also misleading as non-coded amino acids are also commonly found in significant quantities in proteins, such as hydroxylysine 3 and hydroxyproline 4 in collagen. More accurately, the primary proteinaceous amino acids include those coded for in the process of ribosomal translation of DNA via RNA, while secondary proteinaceous amino acids arise from posttranslational modifications (acylation, phosphorylation, sulfation, glycosylation, hydroxylation, oxidation, nitration, methylation, prenylation) of residues, and tertiary from posttranslational cross-linking of two amino acids.6 In contrast, the non-protein amino acids are “those amino acids which are not found in the protein main chains either for lack of a specific transfer RNA and codon triplet or because they do not arise from protein amino acids by post-translational modification”.7 Many of these non-protein amino acids are formed as 2 ACS Paragon Plus Environment

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secondary metabolites in bacteria, fungi, plants, or marine organisms, such as the complex amino acid MeBmt 5 in the fungal product and immunospressant drug cyclosporine A. Finally, chemists have synthesized an incredible array of non-naturally occurring examples (‘unnatural’ amino acids), using a wide variety of synthetic approaches.8 In combination, these ‘unusual’ amino acids possess a wide range of properties9, and are indispensable to the modern medicinal chemist. Scheme 1. Naturally Occurring Unusual Amino Acids

This perspective will describe a range of approved and clinical stage drugs that incorporate amino acids with unusual structures, and discuss medicinal chemistry drug discovery and development programs that rely upon unusual amino acids for optimization of activity. The definition of ‘unusual’ is somewhat arbitrary – for the purposes of this article it will not include D-amino acids (although their presence will be noted in molecules that contain other unusual amino acids; they are often incorporated into peptides to reduce proteolysis), deuterated amino acids (incorporated to reduce metabolism or racemization), or radiolabeled 3 ACS Paragon Plus Environment


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amino acids (other than a few examples of those used clinically; they are often used for metabolite studies). The β-, ɣ- and δ-amino acids, while forming important components of drugs such as anticancer agents paclitaxel (Taxol) 6 (containing phenylisoserine) and ubenimex/bestatin 7 (3-amino-2-hydroxy-4-phenylbutanoic acid), the Merck DPPIV inhibitor sitagliptin (Januvia) 8 (3-amino-4-(2,4,5-trifluorophenyl)butanoic acid), attention deficit hyperactivity disorder therapeutic Methylphenidate (Ritalin) 9 (2-phenyl-2-(piperidin-2yl)acetate), and anticonvulsant gabapentin 10 (1-(aminomethyl)cyclohexaneacetic acid), are generally beyond the scope of this perspective. Scheme 2. β- and γ-Amino Acids in Drugs

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2. UNUSUAL AMINO ACIDS IN DRUGS Drugs containing unusual amino acids can be broadly separated into five different categories that represent a continuum of variation, ranging from drugs consisting of only the zwitterionic amino acid, those with an N- and/or C-terminal modified amino acid core (including di-peptides), longer peptides, proteins containing one or two unusual amino acids, highly modified peptidomimetic peptides, and complex small molecules with an embedded amino acid component.

2.1. Free Amino Acids. There are a range of approved drugs and bioactive molecules that consist of only an amino acid (Schemes 3-7). Many of these are excitatory amino acids (Scheme 3) that mimic the effects of natural amino acids such as L-glutamic acid (Glu) 11, the major excitatory neurotransmitter in the central nervous system (CNS). The excitatory amino acids act on four major classifications of glutamate receptors: N-Methyl-D-aspartic acid (NMDA) receptors, 2amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA) receptors, kainate receptors, and the metabotropic glutamate receptors. These receptors either directly or indirectly activate ion channels in the membrane. NMDA receptors are involved in neuroexcitatory transmission effects mediated by L-Glu or NMDA (2), and have been intensively probed with a wide range of agonists and antagonists.10 Many of the Asp/Glu analogs are conformationally constrained dicarboxylic amino acids based on proline or 1aminocycloalkyl-1-carboxylic acid skeletons. A range of complex bioactive amino acids have been identified from natural products, often with toxic effects, such as kainic acid 12 from seaweed or domoic acid 13, a neurotoxin produced by algae but responsible for amne5 ACS Paragon Plus Environment


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sic shellfish poisoning. Hundreds of analogs have been synthesized, with a number of highly constrained bicyclic derivatives reaching clinical trials. 14 (LY404039) a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors, showed efficacy in schizophrenia when dosed as a prodrug 15 (LY2140023).11,12 More recent studies have focused on a spirocyclopropane version, 16 (LY2934747).13 The Taisho company has developed 17 (MGS0028) as an mGluR 2 receptor agonist with potential use for schizophrenia and anxiety; it is a fluorinated analog of another Lilly compound, 18 (LY354740).14 Stereochemistry is important: the 4 diastereomers of 4-methyl-Glu 19 (Scheme 3) were tested as selective probes of kainate receptors, with the (2S,4R)-isomer having an IC50 comparable to kainic acid itself, with high selectivity for the KA receptor subtype.15 Similarly, all 16 stereoisomers of 2-(2’-carboxy-3’-phenylcyclopropyl)-Gly 20 were evaluated as ligands for several classes of excitatory amino acid receptors, in addition to glutamate transport systems,16 while a series of 79 α-substituted analogs of 3,4-methano-Glu 21 were tested as mGluR antagonists in 1998.17,18 The Kentucky coffee tree Gymnocladus dioicus has attracted attention as the trees are not attacked by insects, its leaves have been used in insecticidal preparations, and the leaves and pods have been reported to be toxic to mammals. Examination of extracts of the pods, seeds, and leaves revealed no toxic amino acids, but the 2S,3S,4R)- and (2S,3R,4R)-diastereomers of 3-hydroxy-4-methyl-Glu 22 were isolated.19


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Scheme 3. Free Excitatory Imino Acids

Heteroaryl isoxazole amino acids (Scheme 3) have attracted a great deal of attention due to their potential as Glu and Asp bioisosteres, with a number of isoxazole derivatives identified as highly active and, more importantly, selective agonists/antagonists of various excitatory amino acid (EAA) receptors. AMPA 23, a bioisostere of Glu, is a highly selective AMPA agonist.20

The corresponding Asp bioisostere, 2-amino-2-(3-hydroxy-5-methylisoxazol-4-

yl)acetic acid (AMMA) 24 is a specific agonist of NMDA receptors.21 7 ACS Paragon Plus Environment


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Heterocyclic amino acid side chains also possess excitatory amino acid receptor activity. (S)-Quisqualic acid 25, isolated from the seeds of Quisqualis indica, is the active ingredient of the ancient Chinese drug Shihehuntze.22 It interacts with a variety of excitatory amino acid receptors, including AMPA, kainate and group I metabotropic glutamate receptors. αMethylation of (S)-quisqualic acid converted its potent agonist activity into antagonist activity for group II metabotropic glutamate receptors.23 D-Cycloserine 26, a partial NMDA agonist, has been tested in humans as a potential therapy for obsessive-compulsive disorder.24 Amino acids with phosphonic acid side chains are also active at excitatory amino acid receptor. Racemic cis-4-(phosphonomethyl)piperidine-2-carboxylic acid, Selfotel 27 (CGS 19755) is a competitive NMDA antagonist that underwent clinical trials for treatment of serious traumatic brain injury and stroke.25 A well-known free amino acid drug is L-Dopa (L-3,4-dihydroxy-Phe) 28 (Scheme 4) the natural precursor of dopamine, which is used therapeutically (as levodopa) to increase dopamine concentrations for the treatment of Parkinson's disease.26 The development of the first synthetically useful asymmetric hydrogenations was driven by their application to the commercial production of 28, as outlined in the 2001 Nobel prize lecture of William S. Knowles.27 Other aromatic amino acids used medically include the hormone thyroxine, O(2,6-diiodo-4-phenol)-3’,5’-diiodo-Tyr 29, available commercially as levothyroxine (Synthroid) to treat thyroid hormone deficiency.28 Secreted by the thyroid gland into the blood, it is responsible for regulating the body’s metabolic rate. 4’-Hydroxy-phenylglycine 30 (oxfenicine) is employed therapeutically to promote carbohydrate oxidation following 8 ACS Paragon Plus Environment

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myocardial infarction.29 Melphalan (Alkeran), or 4'-[bis(2-chloroethyl)amino]-L-Phe 31, is a cytotoxic compound which is used for the chemotherapy of solid tumours. 30 Scheme 4. Aromaticand Heteroaromatic Free Amino Acid Drugs OH

OH

I O

I

I

OH

OH H2N

CO2H

H2N

28

N Cl

CO2H

H2N

29 levothyroxine (Synthroid)

L-DOPA

Cl

CO2H

H2N

30

CO2H 31 mephalan (Alkeran)

L-4'-hydroxy-Phg

OH OH O

H2N

HN

HN

CO2H

32 L-Trp L-tryptophan

H2N

CO2H

33 L-kynurenine 2'-amino-4-oxo-Hfe

OH

N

O H2N

OH

H2N

CO2H

H2N

34 5'-hydroxy-L-Trp

N

CO2H

H2N

CO2H

35 mimosine ( also leucenol)

Trp 32 is used medically as an antidepressant and sleep inducer.31 Metabolism of Trp results in kynurenine (4-keto-2’-aminohomophenylalanine) 33, which was orginally isolated by injecting a rabbit with 4g of L-Trp per day for 4 days, then collecting crystals from acidified urine.32 Trp in the brain is converted into serotonin, with the first step being oxidation to 5’-hydroxy-Trp 34 by tryptophan hydroxylase. 5’-Hydroxy-L-Trp was found to suppress food intake in stressed rats, presumably as the release of brain serotonin is known to affect satiety.33 Mimosine, (also called leucenol) 35 is an amino acid with defleecing properties isolated from Mimosa pudica and Leucaena glauca. Mimosine inhibits the growth of new hair, resulting a net loss of hair due to the normal loss of resting hair. This phenomenom 9 ACS Paragon Plus Environment


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was observed in animals and native woman consuming the seeds of these plants as early as 1897.34 The metalloenzyme nitric oxide synthase (NOS) is the enzyme responsible for the production of nitric oxide by oxidation of L-Arg, with NG-hydroxy-L-Arg 36 (Scheme 5) an intermediate.35 Overproduction of NO is implicated in a range of physiological problems, such as strokes, migraine headaches, rheumatoid arthritis, and Alzheimer's disease,36 so there is considerable interest in NOS inhibitors. NG-methyl-L-Arg acetate (tilarginine acetate) 37 was taken into into Phase III clinical trials in 2005 by ArgiNOx Pharmaceuticals for treatment of cardiogenic shock (myocardial infarction), but the trial was terminated at the 50% review stage due to 50 µM); the free amino acid 65b (882896) was inactive.64 An arylalanine analogue of Trp is found as the central residue in calcitonin gene-related peptide (CGRP) antagonists under development by Bristol-Myers Squibb to treat migraine. Attempts were made to modify an initial lead suitable for intranasal dosing, 66 (BMS-694153), to improve ADMET properties by varying the C-terminal components.65 An O-methyl Ser residue forms the central scaffold of lacosamide 67,66 N-acetyl Omethyl–D-Ser benzyl amide, an anticonvulsant that was approved in the EU and US in 2008. It is believed to act through voltage-gated sodium channels. The shorter analog of Ser, αhydroxy-Gly, is found at the core of 15-deoxyspergualin 68. This antitumor antibiotic isolated from the bacteria Bacillus laterosporus possesses immunosuppressant activity, and is used clinically to prevent renal graft rejection.67 The development of clinical candidate 69

(ACT-246475), a P2Y12 antagonist for treatment of adverse atherothrombotic events, relied on replacement of a Glu residue in a peptide with a phosphonic acid side chain. The compound

exhibited

nanomolar

potency

in

a

platelet

aggregation

assay.

Its

bis[(isopropoxycarbonyl)oxy] prodrug 70 (ACT-281959) was examined in human testing, providing higher exposure of unmasked 69.68 Conformationally contrained imino acids are popular in both drugs and exploratory research programs (Scheme 8). Bupivacaine 71 is a local analgesic consisting of racemic pipecolic acid (Pip, ring-expanded proline) that has been N-butylated and amidated with 2,617 ACS Paragon Plus Environment


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dimethylaniline; the S-enantiomer 72 was subsequently marketed as levobupivacaine.69 The cardioprotective nucleoside transport blocker draflazine 73 contains a piperazine-2carboxylic acid amide with both imino nitrogens (two potential diversity points) Nalkylated.70 The antibiotic clindamycin 74 is a chemically modified (chlorinated) version of the natural product, lincomycin 75, with improved antimicrobial activity and pharmacokinetics,.71 Both contain an N-methyl 4-n-propyl-Pro residue. This imino acid has been varied in a large set of analogs with 4, 6- or 7-membered ring systems (Scheme 8). The ethylsubstituted pipeocolate analog (pirlimycin, Pirsue) 76 showed the best activity, and is used in the treatment of mastitis in cattle.72 The side chain amine of 4-aminoproline provides a useful additional diversity point, with the imino acid employed as the core scaffold in a DNA-encoded library to identify direct InhA inhibitors as potential antitubercular agents; an initial hit was converted into compound 77 with in vivo efficacy.73 An azetidine-2-carboxylic acid group, the ring-contracted analog of Pro, forms the core of an agonist of the G-protein bile receptor 79, which showed efficacy at reducing peak glucose levels in genetically obsese mice, and was derived from a piperidine-3-carboxylic acid screening hit 78.74 The potential complexity of imino acids developed during a drug discovery campaign is illustrated by a series of substituted Pro derivatives 8081 that were effective inhibitors of integrin leukocyte function associated antigen 1 (LFA-1) in cell-based assays, with potential for cancer therapy.75


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Scheme 8. Unusual Amino Acids as Central Components: Imino Acids

Conformational constraints are also introduced by using α,α-disubstituted amino acids (Scheme 9), which have the additional advantage of being not being susceptible to racemization, and less prone to proteolysis when included in peptides. Decernotinib 82 (VX-509), a selective Janus tyrosine kinase 3 (JAK3) inhibitor for the treatment of autoimmune diseases, 19 ACS Paragon Plus Environment


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contains a central 2-amino-2-methylbutyric acid residue.76 The α-disubstitution can be combined with cyclisation of the side chains to form cyclic amino acids: aminocyclobutane1-carbxylic acid anchors the HCV NS5A polymerase inhibitor 83 (BILB 1941), the first allosteric non-nucleoside inhibitor of its class to reach the clinic.77 A cathepsin C inhibitor 84 developed by AstraZeneca as a potential clinical candidate lead consists of a dipeptide with a morpholino cyclic amino acid and biphenylalanine nitrile active site warhead.78 Clinical candidate 85 (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases that inhibited tumor growth in a breast cancer xenograft model, is based around a piperidine-4-amino4-carboxylic acid central residue.79 The same amino acid forms the core structure of opioid agonists carfentanil 86 and remifentanil 87, useful as anaesthetics.80,81 α-Substitution has also been applied to imino acids. 88 (BMS-754807) is a small molecule insulin-like growth factor (IGF-1R) kinase inhibitor that completed a number of Phase 2 studies for oncology indications; it contains a central α-methyl-Pro residue.82 An α-methyl azetidine-2-carboxylic acid residue forms the center of a potent FFA2 (free fatty acid receptor 2, GPR43) antagonist 89 (GLPG0974) that inhibits acetate-induced neutrophil migration and has completed a Phase 2 study for ulcerative colitis, the first FFA2 antagonist to reach the clinic.83


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Scheme 9. Unusual Amino Acids as Central Components: α,α α-Amino Acids

2.3. Unusual Amino Acids in Cyclic Peptides. Natural peptide ligands are increasingly being converted into drugs, with unusual amino acid substitutions being used to increased potency and improve pharmacokinetic properties, particularly by reducing proteolytic susceptibility. Incorporation of unusual amino acids can be used to constrain structures to mimic the active conformation of endogenous ligands, with bulky residues used to sterically block proteolysis.84 Peptide drugs are often cyclic (Schemes 10-13) to provide additional conformational constrains and prevent exopeptidase proteolysis,



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with cyclisations generally achieved by head to tail lactam linkages, tail to side chain amide or ester (depsipeptide) formation, or side chain to side chain connections (e.g. disulfides). A number of natural peptide hormones are cyclic peptides, using Cys to Cys side chain disulfide linkages for constraint, such as somatostatin 90, oxytocin 91, and closely related vasopressins 92 (Scheme 10). Cyclic peptide drugs range from those containing a single nonnatural amino acid substitution to heavily modified analogs with multiple substitutions. An example of the first is lanreotide 93,85 a somatostatin receptor agonist used to treat acromegaly with a D-2’-naphthylalanine residue. In contrast, pasireotide 94,86 a cyclic hexapeptide analog of the hormone somatostatin for the treatment of Cushing's disease, contains Obenzyl Tyr, acylated hydroxyproline, and phenylglycine residues.

Scheme 10. Cyclic Peptide Hormones and Unusual Amino Acids in Cyclic Peptides H-Ala-Gly-Cys-Lys-Asn-Phe-PheTrp-Lys-Thr-Phe-Thr-Ser-Cys-OH (disulfide bridge Cys3-Cys14) somatostatin 90 HO D-aa HN

NH2

H-Cys-Tyr-Ile-Gln-AsnCys-Pro-Leu-Gly-NH2 (disulfide bridge Cys1-Cys6) oxytocin 91

NH

OH NH O 2 NH OHS S cystine disulfide NH NH2 NH O D-aa HN NH D-aa OHO D-aa O

H N

H N

O

HN

H-Cys-Tyr-Phe-Gln-AsnCys-Pro-Arg-Gly-NH2 (disulfide bridge Cys1-Cys6) Arg vasopressin 92

HN

O

NH H2N

O

N

O O O O O O

D-aa NH

HN NH NH2

93 lanreotide

HO

94 pasireotide


O

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Many antibiotics in clinical use are cyclic peptides containing unusual amino acids (Scheme 11). The natural product-derived cyclic depsipeptide quinupristin 95 (used in combination with dalfopristin as part of the antibiotic Synercid87) contains Phg, D-2aminobutyric acid (D-Abu), N-methyl-4’-dimethyl-Phe, and an S-alkylated 4-oxo-5thiomethylpipecolic acid residue. L-Threo-β-methyl-Glu and kynurenine are components of the cyclic lipopeptide antibiotic daptomycin 96, isolated from Streptomyces roseosporus. Daptomycin was approved in September 2003 as the first member of a new class of antibiotics, acting against most clinically relevant Gram-positive bacteria (including drug resistant strains) via disruption of multiple membrane functions.88 The polymyxin antibiotics colistin 97 and polymyxin B 98 contain five 2,4-diaminobutyric acid residues.89 N-methyl 4’dimethylamino-L-Phe, D-Abu, Phg and 4-ketopiperidine-2-carboxylic acid are found in mikamycin B (streptogramin A, pristinamycin IIA) 99, a depsipeptide antibiotic isolated from Streptomyces mitakaensis90 that forms one component of the combination drug pristinamycin. Pristinamycin is used primarily for the treatment of staphylococcal infections: the other component (pristinamycin IA) is a macrolide, with the two together having a synergistic antibacterial action producing a similar spectrum of action to erythromycin.



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Scheme 11. Unusual Amino Acids in Cyclic Peptide Antibiotics

Aromatic amino acids feature prominently in a number of cyclic peptide antibiotics (Scheme 12). Complex biaryl ether aryglycines are found in the vancomycin 100 glycopeptide class of antibiotics, which contain a central 3',4',5'-trihydroxy-Phg unit that forms the connecting point for the glycosyl portion of the molecule and creates the CD and DE ring systems via two biaryl ether linkages to the phenol of Tyr or β-hydroxy-3’-chloro-Tyr residues. A 4’-hydroxy-Phg and 3’,5’-dihydroxy-Phg residue form the AB ring system via a 24 ACS Paragon Plus Environment

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biaryl linkage. Recently, three additional glycopeptide antibiotics have been approved, dalbavancin 101, telavancin, and oritavancin 102, with the latter two containing the same core ring systems as vancomycin, and dalbavancin possessing an additional biarylether-linked cyclic Phg ring system, similar to the natural product teicoplanin.91 A number of homologs of arylalanines are found in cyclic peptide antibiotics, such as 3hydroxyhomotyrosine or 3,4-dihydroxyhomotyrosine in the antifungal cyclic lipopeptides echinocandin B 103 and echinocandin D 10492 along with Orn or 3,4-dihydroxy-Orn, 4hydroxy-Pro and 3-hydroxy-4-methyl-Pro. The semisynthetic clinical analogs anidulafungin 105, caspofungin 106, and micafungin 107 have very similar structures, varying only in the hydrophophobic tail for 105 and with 3-hydroxy-Orn and 3-hydroxy-4-amino-Orn residues in 106, and 3-hydroxy-Gln and sulfated 3’,4’-dihydroxy-3,4-dihydroxy-Hfe in 107.93



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Scheme 12. Unusual Aromatic Amino Acids in Cyclic Peptide Antibiotics


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Many β-hydroxy amino acids are found in peptide antibiotics, generated by enzymatic hydroxylation of the β-carbon by β-hydroxylases found in nonribosomal peptide synthetase clusters., with further modifications by glycosylation, oxidation, retro-aldol cleavage, or macrolactonization.94 For example, in addition to the examples already shown above, (2S,3R)-β-hydroxy-Leu is a component of the macrocyclic peptide lactone antibiotic lysobactin 108, along with β-hydroxy-Asn and β-hydroxy-Phe (Scheme 13).95 Glycosylated erythro-β-hydroxy-His is found in the bleomycins 109, acyclic glycosylated peptide antitumor antibiotics isolated from Streptomyces verticillus in 1966 and now used clinically to treat carcinomas.96 The closely related cleomycin also contains β-hydroxy-His, with an α-(1hydroxycyclopropyl)-Gly residue (cleonine) 110 replacing Thr.97 MeBmt 5, (4R)-[(E)-but-2enyl]-4,N-dimethyl-L-threonine, is an essential component of the widely used cyclic undecapeptide immunosuppressive drug cyclosporine A (CsA) 111.98 One strategy to increase the plasma stability of disulfide-containing cyclic hormones such as 90-92 is to replace the unstable disulfide linkage with more stable moieties. For example, selenocysteine 112 and tellurocysteine 113 (Scheme 14), have been used to replace Cys residues in disulfide-cyclised peptides, leading to more stable analogues, such as in oxytocin analogues.99 Lanthionine 114 is a thioether analog of disulfide-bridged cystine, with a oneatom shorter bridge. The nisin group of polycyclic peptide antibiotics isolated from Streptococcus lactis contain both 114 and cystathionine 115 (the homolog of lanthionine which corresponding to the cystine chain length), as well as the cystathionine regioisomer methyllanthionine 116 (a thiol bridge between the β-position of Abu and the β-position of Ala).100 27 ACS Paragon Plus Environment


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Scheme 13. Unusual Hydroxy Amino Acids in Naural Product Peptides O

108 lysobactin

H2 N O

-hydroxy-Phe HO

N H NH

O

H2N HN

O

O

OH O

depsipeptide

HN

O

HN

H N

N H

NH

O

O

O

-hydroxy-Asn

OH

H N

N H

O HO

O

O NH

-hydroxy-Leu HN H2 N

O

NH2

H N N

NH2

O

H2N

HO O

HN O HO

NH

O

N H N

N

O

H N

O

H N

S+

O

N

NH2

S

N S

OH

OH N H

O OH

109 bleomycin A2

OH

H2 N

OH OH OCONH2

OH

110 cleonine component of cleomycin antibiotics

HO O N

N

N

O O

N D-aa H

CO2H

O

H N

N

O

O

O

O

N O

H N

N O

N

H N O

111 cyclosporine A


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Carbon-linked diaminodicarboxylic acids are useful as stable replacements for a cystine peptide bridge, with the application of diaminodicarboxylic acids for intermolecular peptide cross-linking reviewed in 2016.101 The best known alkyl-linked diaminodicarboxylic acid is 2,6-diaminopimelic acid (DAP) 117 (Scheme 14), which is found in bacterial cell walls as an integral component of peptidoglycan. 2,7-Diaminosuberic acid 118 corresponds to the allcarbon analog of a Cys-Cys bridge or cystathionine 115, and in one study was used to link two symmetrical peptides that were effective as hematoregulatory peptides. A number of analogs were synthesized with 118 replaced by other bridge lengths, including 117, 2,5diaminoadipic acid 119 and 2,9-diaminosebacic acid 120; the analog with 119 was 1000-fold more active than the original 118-based peptide.102 Scheme 14. Unusual Amino Acids used for Peptide Cyclization



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Diamino acids can be used to form lactam bridges with the C-termini or Asp/Glu side chains of peptides. Lys is most commonly used, but can be substituted with the shorter chain analogs Orn 121, 2,4-diaminobutyric acid (Dab or 2,4-Dab) 122 (not to be confused with 2,3-diaminobutyric acid, DABA, 123) and 2,3-diaminopropionic acid (Dap) 124 (Scheme 14). For example, the side chain of Dab was used to cyclize with the C-terminus of enkephalin analogs, producing highly potent derivatives.103 A lactam linkage between the side chains of Dap and Asp replaced the disulfide linkage in the cyclic peptide hormone oxytocin, resulting in weak, but still active, analogs.104 Cyclic lactam analogs of α-melanotropin were prepared via lactam formation between the side chains of Asp or Glu at position 5 with the side chain amino group of Lys, Orn, Dab or Dap at position 10. The 23-membered lactam rings gave the best results.105 Dap and Dab were employed as replacements for an unstable

β-hydroxy-Asp residue that forms a depsipeptide linkage in the cyclic lipoglycodepsipeptide antibiotic ramoplanin. The aglycon analog with Dap substitution was more potent and considerably more stable than the parent aglycon, while substitution with the homologous Dab resulted in complete loss of activity.106 Another class of diaminodicarboxylic acids are linked via aryl moieties, the best known being isodityrosine 125 (Scheme 15) which contributes to cross-linking of plant cell wall glycoprotein107 and was only discovered in 1982.108 As previously shown, the glycoeptide antibiotics 100-102 contain a series of biaryl- and biaryl-ether bridged diamino dicarboxylic acids. Highly active bicyclic analogs of the peptide hormone somatostatin were prepared using a

naphthyl-bridged

diaminodicarboxylic

acid,

1,5-bis[3-(2-aminopropanoic

ac-

id)]naphthalene 126 to form one of the bridges.109 An imidazole-bridged diaminodicarbox30 ACS Paragon Plus Environment

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ylic acid is contained in theonellamide F 127, an antifungal bicyclic dodecapeptide isolated from a marine sponge; 4’-bromo-Phe is another unusual amino acid in this peptide.110

Scheme 15. Diaminodicarboyxlic Acids for Cyclic Peptide Bridges

Alkene side chains of amino acids within peptides have been linked together by crossmetathesis to form cyclic systems. These ‘stapled peptides’ are the key technology behind biotech company Aileron Therapeutics, where they are used to bridge turns in helical peptides, stabilising the secondary stucture. In early efforts, O-allyl-Ser 128 and O-allylhomoserine 129 (Scheme 16) residues within a helical peptide were crosslinked by a Rucatalyzed metathesis reaction to give cyclic helical peptides.111 Subsequently, (R)- and (S)-

α-allyl-Ala 130 and the homologous α-[(CH2)nCH=CH2]-Ala residues 131 (n = 2,3,4,6) were incorporated into α-helical peptides at the i,i+4 or i,i+7 positions in a combinatorial fashion. Ruthenium-catalyzed ring closing metathesis was then employed to attempt to crosslink residues in a favorable conformation, with the goal of stabilizing helix formation 31 ACS Paragon Plus Environment


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and improving peptide metabolic stability.

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Certain combinations of residues/positions

showed no crosslinking, while other couplings went to near completion, with a large 34membered macrocycle forming rapidly and efficiently (12 carbons in the metathesized crosslink).112 This same approach was applied to design cell-permeable HIV-1 integrase inhibitors.113 Pairs of allylglycine 42 residues have been metathesized to replace either of the two disulfide linkages in α-conotoxin RgIA, an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and inhibitor of high-voltage-activated N-type calcium channels. The analogs retained activity with different selectivity patterns, and had improved serum stability.114 An alternative method to constrain peptides is to use the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) ‘click’ chemistry reaction between azides and alkynes.84 A number of different azido amino acids and alkyne amino acids were used to create a 160,000 member macrocyclic pentapeptide library 132 derived from DNA-programmed chemistry with the CuAAC reaction used for cyclisation. Screening identified XIAP inhibitors which were optimised to produce a complex dimeric macrocycle 133 (with two triazole linkages) that shrunk tumors in a mouse xenograft model.115 Analogs of the melanocortin receptor agonist MTII, a cyclic peptide, have been prepared using β-azido-Ala 134, γ-azido-Abu 135, δazido-Nva 136 and ε-azido-Nle (azido-Lys) 137, coupling with 2-aminooct-7-ynoic acid 138, 2-aminohept-6-ynoic acid 139, 2-aminohex-5-ynoic acid 140 and propargylglycine 141 residues respectively, incorporated at i and i+5 position to maintain a common chain length and reproduce a type I β-turn.116


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Scheme 16. Unusual Amino Acids Used to Form Cyclic Peptides via Metathesis or Dipolar Cycloaddition

2.4. Unusual Amino Acids in Linear Peptides. Important linear peptide hormones include bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-PheArg) 142, angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) 143, neurotensin (pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu)

144,

gonadotropin-releasing

hormone (GnRH, also known as follicle-stimulating hormone–releasing hormone, FSH-RH, 33 ACS Paragon Plus Environment


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and luteinizing hormone–releasing hormone, LHRH: pyroGlu-His-Trp-Ser-Tyr-Gly-LeuArg-Pro-Gly-NH2) 145 and the enkephalins, Met-enkephalin (Tyr-Gly-Gly-Phe-Met) 146 and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) 147. (Scheme 17).

Many linear peptide drugs (Scheme 17) possess D-amino acids at the N- or C-termini, to reduce proteolysis. The decapeptide icatibant 148117, a selective antagonist of bradykinin B2 receptors for treatment of acute attacks of hereditary angioedema, is N-terminally capped with D-Arg, and also has 4-hydroxy-Pro, 2’-thienylalanine, tetrahydro-isoquinoline-3carboxylic acid (Tic) and octahydroindole-2-carboxylic acid (Oic) residues. Metastin/kisspeptin is a 54 residue peptide ligand of the KISS1R receptor that regulates GnRH secretion. Takeda reduced this to a stable nonapeptide, [D-Tyr46, D-Pya(4)47, azaGly51, Arg(Me)53] metastin(46−54) 149, with pyridylalanine, azaglycine and methylated Arg residues. The analog reduced plasma testosterone in male rats. A series of clinically used analogs of GnRH 145 illustrate different approaches to linear peptide modifications. The nonapeptide histrelin 150 is very similar in structure to GnRH 145, retaining the N-terminal pyroglutamate residue that reduces proteolysis, truncating the C-terminal Gly to an ethyl amide of the preceeding Pro, and replacing the central Gly residue with an Nim-diphenylmethyl-D-His 118 It is used to treat hormone-sensitive cancers of the prostate in men and uterine fibroids in women. In contrast, cetrorelix 151 has a highly modified decapeptide structure, with only 4 unmodified residues. An N-terminal D-2’-Nal replaces the pyroglutamate-1 of GnRH 145, 4’-chloro-Phe for His-2, D-3’-pyridylalanine for Trp-3 and D-citrulline (Cit) for central Gly-6. The C-terminal Gly is replaced by a proteolytically 34 ACS Paragon Plus Environment

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resistant D-Ala terminus. Cetrorelix is marketed for use both in in-vitro fertilization by inhibiting premature luteinizing hormone surges and to treat hormone-sensitive prostate and breast cancers.119 Closely related abarelix 152,120 is another modified decapeptide used in oncology to reduce the amount of testosterone made in patients with prostate cancer. Like 151, it has 3 D-2’-Nal, 4’-chloro-Phe, D-3’-pyridyl-Ala, N-methyl-Tyr, but replaces the citrulline with D-Asn and Arg with Nε-isopropyl-Lys. The steric crowding of α,α-dialkylglycines can provide proteolytic resistance in peptides. Glucagon-like peptide-1 (GLP-1) analogues have found widespread use for the treatment of diabetes. Taspoglutide is a 30-mer GLP-1 analog with sterically bulky α-aminoisobutyric acid (Aib) 153 near the N- and C-terminal amino acids to reduce proteolysis.121 Devloped by Roche, it failed in Phase 3 trials due to side effects. α,α-Diethylglycine has replaced Gly in an analog of a Pro-Leu-Gly-NH2 tripeptide 154 (Scheme 18). The new tripeptide was 10 times more potent than the Gly analog at increasing the agonist response of the dopamine receptor.122

Scheme 17. Linear Hormones and Unusual Amino Acids in Linear Peptides



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Tyr-Gly-Gly-Phe-Met Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Met-enkephalin bradykinin pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu 146 142 neurotensin 144 Tyr-Gly-Gly-Phe-Leu Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Leu-enkephalin angiotensin II pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 147 143 luteinizing hormone-releasing hormone (LHRH) 145 HN 148 icatibant

Oic octahydroindole-2carboxylic acid

NH2 NH

H2N

O

O N

N

O

NH

O

O

H N

N H

O

N

N O D-aa

O HO

HO

HN H2N

NH2

S

D-aa H N

HN

N H

CO2H

Tic tetrahydroisoquinoline3-carboxylic acid

H2N NH H2N D-aa O

149 metastin(46-54) analog

O H N

O

H N

N H

O

H N

N H OH

O

O

O N H

O

H N

N H

O

NH HN NH2

HN H N

H N

O

N H

N

N H N

O

OH H N

O N H

O

pyroglutamate

2

O

azaGly

N

150 histrelin

NH

N H

O

D-aa N H

O NH

N H

Me

NH

N H N

O N H

O

N O

O

HN

OH O NH2 Cit citrulline NH

Cl 151 cetrorelix

D-aaO H N O

N H

O

H N

N H

O

OH H N O

O

D-aa N H

H N O

HN

NH2 NH

O N H

N O

O

D-aa N

N H

D-aa NH2 O

OH HN

Cl D-aa O H N

152 abarelix O

N H

H N

O OH

O

O

N H

N O

D-aa

NH2 O H N

O N H

O

D-aa N

OH


N H

N O

O

N H

D-aa NH2 O

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Another strategy recently reported to make potential peptide therapeutics resistant to proteolytic degradation involves incorporation of sterically hindered amino acids at the P1′ position (C-terminal side of potential enzyme cleavage sites); bulky β,β-dimethyl-Asp and tertLeu were used to demonstrate the potential general utility of this approach. Multiple substitutions were made to GLP-1 as an example, making it resistant to dipeptidyl peptidase IV and five other proteases.123 Cyclic α,α-dialkylamino acids such as ACC 155, ACBC 156, ACPC 157, and ACHC 158 have been incorporated into many peptides to introduce conformational constraints, as have the 2,3-methano-analogs 159 and 160 of many amino acid. For example, 4 isomers of 1amino-2-phenylcyclopropane-1-carboxylic acid (2,3-methano-Phe, 2-Ph-ACC) were used as constrained Phe analogs in analogs of enkephalins, with only the Z-substituted derivatives showing binding affinity.124 2-Aminoindane-2-carboxylic acid 161 was used to replace Phe in angiotensin II analogs, creating a potent angiotensin II inhibitors with low pressor activity.125 Imino acids also provide contraints to linear peptides, particularly bicycic derivatives. Oic, already seen in 148, was incorporated into the tripeptide ACE inhibitor perindopril 162,126 bradykinin receptor antagonists127 and antagonists of the NK-1 receptor,128 as was (S,S,S)-2azabicyclo[3.3.0]octane-3-carboxylic acid (Aoc) 163.128 A new bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold was developed as a Pro analog and combined with difluorocyclohexylglycine to form an antagonist 164 of inhibitor of apoptosis proteins (IAPs) that caused tumor regression in a MDA-MB-231 tumor xenograft model.129 37 ACS Paragon Plus Environment


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Scheme 18. Sterically Hindered and Conformationally Constrained Amino Acids

2.5. Diverse Amino Acids Employed for Peptide SAR Studies The breadth of amino acid structures that medicinal chemists have employed for developing new drugs is well exemplified by examining those tested during peptide SAR campaigns. Alkyl. The range of amino acids with alkyl side chains (Scheme 19) includes the Ala homologue 2-aminobutyric acid, Abu 165, which is often used as a hydrophobic and metabolically stable Ser/Cys replacement. Two Abu residues are contained in birinapant 166, a secondgeneration bivalent antagonist of IAP proteins that is currently undergoing clinical development for the treatment of cancer,

130

A variety of hydrophobic alkyl amino acids (including

Ala, 165, norvaline (Nva, often used as non-oxidisable Met replacement) 166, norleucine 38 ACS Paragon Plus Environment

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(Nle) 167, Val, Leu, Ile, and Tle 62) were used to demonstrate that peptide binding affinities can be improved with a single non-standard residue, as measured by binding of a hexapeptide to a protein (PSD-95 protein) PDZ domain.131 Peptidomimetic furin inhibitors were prepared with 165, 165, 167, Tle 62, tert-butylalanine (Tba, also known as neopentylglycine) 169, cyclohexylglycine (Chg) 170, adamantylglycine (Adg) 171, cyclopropylalanine (Cpa) 172, and cyclohexylalanine (Cha) 173, replacing the central residue.132 Cha 173 has been widely used as a Phe replacement in a number of peptides such as angiotensin II133 and bradykinin.134. Replacing the Ile5 residue in angiotensin II with Chg 170 produced a more active analog.135 L-Cyclopentylglycine 174 and D- and L-Chg 170 were used as Ile replacements in analogs of the peptide hormone oxytocin,136 as was L-β,β-diethylalanine 175.136 β(1-Adamantyl)alanine 176 and Tba 169 were used as bulky Leu replacements in enkephalin analogs.137 Fluorinated alkyl amino acids are even more hydrophobic. Penta- and heptafluoronorleucines 177-178 have been shown to possess physical properties (described mainly by hydrophobic/hydrophilic properties and variations in side chain size) significantly different from all other previously characterized natural and synthetic amino acids.138 Hexafluorovaline 179 was used to replace either of the two valines contained in angiotensin II. The analogs resisted enzymatic hydrolysis, and one was a potent inhibitor while another was a potent agonist.139 Silyl amino acids have also been incorporated into a number of peptides as hydrophobic amino acid replacements. For example, an analog 180 of the GnRH antagonist Cetrorelix 151 was prepared with β-trimethylsilyl-Ala or β-trimethylgermyl-Ala replacing the Tyr residue, providing similar in vitro activity but an increased duration of effect 39 ACS Paragon Plus Environment


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compared to the all-carbon analog.140 A silaproline derivative 181 was incorporated into a hexapeptide analog of the neuropeptide neurotensin, which retained biological activity, and was more resistant to proteolysis.141 Scheme 19. Alkyl and Hydrophobic Amino Acids


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Aromatic. The greatest diversity of amino acid side chains is found in substituted aromatic amino acids (arylglycine and aryalanines), which been extensively used in SAR studies (Scheme 20). A library of cyclic tridecapeptide inhibitors of nuclear hormone receptors was prepared by testing 37 different amino acids at three positions, including phenylglycine (Phg) 182, 2’- or 4’-fluoro-Phg, 2’,3’-, 3’,4’-, 2’,5’-, or 2’,4’-Phg, and 2’- or 3’trifluoromethyl-Phg.142 Twenty-one different aryl-substituted Phe and Tyr analogs were examined in cyclic octapeptides under development to bind to α3 integrin on MDA-MB-231 breast cancer cells.143 Over 30 analogs of a minimal sequence of the neuropeptide nociceptin were prepared to investigate the role of Phe4, with the Phe replacements including parafluoro, -chloro, -bromo, -iodo, -nitro, -cyano, -trifluoromethyl, -methyl, -methoxy, -phenyl and -amino groups, meta- and ortho-fluoro, conformationally-restricted α-, β- or N- methylPhe, diphenylalanine 183, homophenylalanine 184, Phg 182, 1-naphthylalanine 185, and 2naphthylalanine 186. Several of the analogs with small electron-withdrawing substituents were found to be more potent agonists for the OP4 receptor.144 Both β-naphthyl-Ala regioisomers 185 and 186 have found extensive use as hydrophobic Phe replacements, and have been used to replace Phe in enkephalins (298),145 vasopressin antagonists146 and orally active matrix metalloproteinase inhibitors.147 The D-enantiomers of 185 and 186, along with other hydrophobic Phe analogs, including 3’,4’,5’-trimethoxyPhe, 2’,3’,4’,5’,6’-pentafluoro-Phe, β-(1-bromo-2-naphthyl)-Ala, 3’-trifluoromethyl-Phe, 4’trifluoromethyl-Phe, 2’,4’,6’-trimethyl-Phe, 3’-phenyl-Phe, β-(9,10-dihydro-9-anthryl)-Ala,

β-(2-fluorenyl)-Ala, β-(benzhydryl)-Ala and β-(9-anthryl)-Ala 187, were used as replacements for the Gly-6 residue in analogs of the decapeptide LHRH. The analogs containing β41 ACS Paragon Plus Environment


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(2-naphthyl)-D-Ala or 2’,4’,6’-trimethyl-D-Phe were very potent superagonists.148 Carboranylalanines 60/61 have also been used as a sterically bulky Phe analog. Replacement of Phe in enkephalin analogs provided 2-fold enhancement of morphine-like activity.137

Scheme 20. Aromatic Amino Acids

Dipeptide antagonists of substance P with specificity for the NK-1 receptor were prepared with a number of unnatural aromatic amino acids, such as 3-(6-methyl-2-naphthyl)-Ala, 3(6-chloro-2-naphthyl)-Ala, 3-(5,6,7,8-tetrahydro-2-naphthyl)-Ala 188, and 3-(2,3-dihydro42 ACS Paragon Plus Environment

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1,4-benzodioxin-6-yl)-Ala 189,149 or with a number of conformationally restricted Phe analogs (diphenylalanine 183, 1-indanylglycine 190, 2-indanylglycine 191, 9-fluorenylglycine 192, 1-benz[f]indanylglycine 193, (E)-dehydro-Phe 194 and (Z)-dehydro-Phe) 195.150 Tic 196 is commonly used as a conformationally restricted replacement for Phe, reducing the movement of the aromatic ring as well as the peptide backbone.151 The use of Tic in the conformational design of oxytocin and somatostatin peptide analogs was discussed in 1993.152 Arylalanine derivatives with a β-substituent are of considerable interest as the additional substituent causes conformational restrictions, reducing the number of possible side-chain rotamer populations.153 The four stereoisomers of β-Me-Phe 197a-200a were incorporated into analogs of α-melanotropin, a peptide hormone involved in regulating skin pigmentation and tanning. The potency varied by up to a 1000-fold factor.154 Similarly, the four stereoisomers of β-Me-Phe 197a-200a, β-Me-Tyr 197b-200b and β-Me-Tic have been systematically incorporated into the δ-opioid antagonist H-Tyr-Tic-Phe-Phe-OH, resulting in a profound influence on potency, selectivity and signal transduction properties.155 A range of twelve constrained Phe analogs, including α,α-disubstituted and 2,3-methano derivatives, were used to replace Phe in gramicidin C antibacterial cyclic decapeptides.156 The incredible number of Phe analogs possible is demonstrated by the extensive range of substituted Phe derivatives 201a-bb (Scheme 21) developed as non-hydrolyzable analogs of phospho-Tyr

(pTyr)

201a,

including

4’-phosphonomethyl-Phe

(Pmp)

201b,

4’-

phosphonodifluoromethyl-Phe (F2Pmp) 201c, O-malonyl Tyr (OMT) 201n, O-fluoromalonyl Tyr (FOMT) 201o, and O-carboxymethyl-3’-carboxy-Tyr 201p ,primarily in the quest for



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inhibitors of protein tyrosine phosphatase 1B (PTP-1B) to treat diabetes.157 Most of these were initially incorporated into a heptapeptide 202 peptidic PTP1B inhibitor. Scheme 21. Aromatic Amino Acids: Phosphotyrosine Mimetics

Heteroaromatic. Numerous analogs have been synthesized to make more stable isosteres of the Trp indole ring (Scheme 22). L-Trp, D-Trp, N-methyl-L-Trp, β-(3-benzothienyl)-Ala 44 ACS Paragon Plus Environment

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203, β-(1-naphthyl)-Ala 185 and β-(2-naphthyl)-Ala 186 were used in SAR-studies of matrix metalloproteinase inhibitors, along with other heteroarylalanines.158,159 Conformationally constrained analogs of Trp such as 204-210 were examined in a 1999 review, including discussions on the synthesis, conformational analysis and medicinal chemistry applications of these derivatives.160 Histidine analogs include Nt-methyl-His 211 and β-(imidazol-1yl)Ala 212, which were used for SAR studies directed towards the design of orally active renin inhibitors.161 The key His residue in tripeptide thyrotropin releasing hormone (TRH, pyroGlu-His-Pro-NH2), a hypothalamic peptide that controls the release of thyroid stimulating hormone and prolactin from the pituitary gland, was replaced with a range of analogs. Substitution with Phe resulted in a 10-fold loss of potency,162 but β-(2-thienyl)-L-Ala 213, β(2-furyl)-L-Ala 214 and β-(2-pyrrolyl)-L- and D-Ala 215 gave better results.163 The His-6 residue in Angiotensin II was replaced with Dab 122, 4’-nitro-Phe, 4’-amino-Phe, β-(2pyridyl)-Ala 216 and β-(2-imidazolyl)-Ala 217 in order to examine the roles of the imidazole nitrogens on pressor activity.164 The heteroaromatic amino acid β-(thiazol-4-yl)Ala 218 was used in an orally active renin inhibitor 219 (ABT-517) that was scaled up for clinical development,165 and has been used as the central residue in selective calpain inhibitors.166 βarylthiazole alanines were recently incorporated into analogs of neurotensin 144, replacing Tyr11 and improving plasma stability and selectivity towards NTS1.167



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Scheme 22. Trp and His Analogs

Acidic Side Chains. Homologs of Asp/Glu have been used in analogs of methotrexate 220, (Scheme 23) a close analog of folic acid 221 that binds to the enzyme dihydrofolate reductase and is used as an antitumor agent, with α-aminoadipic acid 222, α-aminopimelic acid 223 or α-aminosubseric acid 224 replacing the Glu residue and retaining activity.168 The tricarboxylic acid, γ-carboxyglutamic acid (Gla) 225 has a malonic acid moiety important for binding Ca2+ to proteins, and for the adsorption of proteins to a phospholipid surface. Gla was used to replace a Glu residue in a cyclic peptide Grb-SH2 domain antagonist.169 46 ACS Paragon Plus Environment

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Scheme 23. Acidic Amino Acids

Basic Side Chains. The guanidine side chain amino acid Arg is the preferred P1 residue of a range of proteolytic enzymes, in particular the coagulation cascade enzymes such as 47 ACS Paragon Plus Environment


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thrombin, Factor VIIa and Factor Xa. However, the presence of the charged guanidine group generally precludes oral availability of inhibitors containing Arg, so a large number of isosteric amino acids have been developed to overcome poor membrane permeability (Scheme 24).170 For example, 3’-amidino-L-Phe 226 was employed as an Arg analog in potent thrombin inhibitors,171 while 4’-amidrazono-Phe 227 gave sub-nM thrombin inhibitors with good oral availability and improved selectivity over trypsin.172 A β-(1-aminoisoquinolin-6-yl)-Ala moiety 228 also gave good activity and improved Caco-2 permeability.173 Isomeric 4’amidino-Phe 229 has also been used as an Arg mimetic, most recently in a dengue protease inhibitor.174 In other studies, L-norarginine 230 was used in analogs of the bioactive peptide adrenocorticotropic hormone (ACTH)175 and 4’-guanidino-L-Phe 231176 and homoarginine 232134 in bradykinin analogs. L-3-(N-amidino-4-piperidyl)-Ala 233 was incorporated into kallikrein inhibitors using a 10-mer cyclic peptide scaffold.177 A 2016 study tested eighteen different Arg analogs as replacements for the central Arg residue in tripeptide plasmepsin IV inhibitors 235 (a potential treatment for malaria); most changes resulted in a complete loss of enzymatic activity, but the analog incorporating canavanine 234 was 13-fold more potent than the Arg-containing peptide in the enzymatic IC50 assay, and 14-fold in a parasite viability assay requiring cellular penetration.178


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Scheme 24. Basic Amino Acids

NH2

N

HN

NH2

NH2

NH2

H2N

CO2H 226 3'-amidino-L-Phe

H2 N

CO2H 227 3'-amidrazono-L-Phe

NH

N

H2 N

CO2H 228 -(1-aminoisoquinolin-6-yl)- L-Ala

NH2

NH2

H2 N

CO2H 229 4'-amidino-L-Phe

HN

NH

H2 N

CO2H 230 L-norarginine

NH2 H2N

NH

HN

NH

NH

N

H2 N

CO2H 231 4'-guanidino- L-Phe

CO2H

H2 N

232

N H

O

H N

CO2H

H N

N H

O

NH

HN

NH

HN

x

HN

HN

NH

x

NH2 NH

NH2 NH

x OH NH

O

NH

x

HN O

x O NH

HN

NH

x

NH2 NH

x

x

NH2

O O S NH

NH

CN NH

HN

CO2H 234

O

x

NH

x

HN

NO2 NH

NH2

NH

L-canavanine

NH

OH O

N

x

x

NH2

O

H2N

HN

235 plasmepsin IV inhibitors

HN

NH2

233 -(N-amidino-piperid-4-yl)- L-Ala

L-homoarginine

R

O O

H2N

NH2

HN

NH

O

NH2 NH

x

HN

HN

NH

NH x

NH2 x

x


x

NH2 NH

x


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2.6. Unusual Amino Acids in Proteins. Amino acids containing substituents amenable to site-selective modification, such as ketone, azide, alkyne, alkene, and tetrazine groups, or other amino acids useful for improving stability or activity, can be specifically incorporated into proteins by using genetic encoding during protein expression.179 The array of bioorthogonal reactions used for site-specific protein labeling and engineering was recently reviewed.180

This site-selective protein-

modification provides opportunities for basic biology studies as well as drug development.181 For example, the derivatizable amino acids 4’-acetyl-L-Phe 236 or 4’-benzoyl-L-Phe 237 (Scheme 25) were incorporated into human superoxide dismutase via use of the nonsense codon TAG and misacylated tRNA in a Saccharomyces cerevisiae system.182 The ketone can then be functionalized via oxime or hydrazone formation: 236 was placed into the Z domain of staphylococcal protein A, then derivatized with either fluorescein hydrazide or biotin hydrazide.183 Azido amino acids 134-137 were all incorporated into the E. coli outer membrane protein OmpC via expression in media depleted of Met and supplemented with the noncanonical amino acid. The surface exposed azido-residues were then employed for a Cucatalyzed triazole formation with an alkyne linked to biotin, then visualized by staining with fluorescent avidin.184 The same methodology can be applied for SAR or mechanistic studies on the effects of specific amino acid replacements in proteins. E. coli has recently been genomically recoded to allow for multi-site incorporation of unusual amino acids, with 14 different Phe derivatives used as examples.185 A series of Trp analogs (5’-methyl-Trp, 4’,-, 5’- or 6’-fluoro-Trp, 50 ACS Paragon Plus Environment

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7’-aza-Trp 238 or β-3-benzothienyl-Ala) 203 were incoporated into thymidylate synthase as replacements for Trp-82 in order to investigate the catalytic role of this residue in hydride transfer.186 Scheme 25. Unusual Amino Acids in Proteins

Site selective modifications will increasingly become important for future protein-based drugs, employed in strategies such as selective PEGylation of proteins to improve pharmacokinetics or for conjugation of small molecule ‘payloads’ to antibodies in antibody-drug conjugates (ADCs). For example, 235 was used as the attachment point to PEGylate human growth hormone at specific locations, improving its pharmacokinetic properties in clinical studies.187, and has also been used to prepare an ADC in which an aminoxy-modified version of the cytotoxic drug monomethyl auristatin was ligated to an anti-Her2 antibody Fab frag-

ment.188 p-Azidomethyl-L-Phe 239 has also been used to ligate auristatin to an antibody, the tumor-specific, Her2-binding IgG trastuzumab (Herceptin), using strain-promoted azide– alkyne cycloaddition.189 51 ACS Paragon Plus Environment


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The unusual amino acids employed in ADCs can also reside on the payload component, such as in Pfizer’s 240 (PF-06650808), an anti-NOTCH3 ADC combining a humanized antibody targeting the NOTCH3 receptor, (overexpressed in a number of human cancers) with an auristatin-based cytotoxic agent. The structure of the aurisatin-like component was tweeted during the Division of Medicinal Chemistry’s First-time Disclosures symposium at the 2016 ACS National Meeting in San Diego, showing an Aib residue along γ-amino acids and other peptidomimetic modifications.190 The Val-Cit (citrulline) dipeptide moiety acts as a cathepsin-cleavable linker group that releases the cytotoxic cargo inside the tumour cell.191

2.7. Unusual Amino Acids in Peptidomimetics. Some peptide leads are so extensively modified that their peptidic nature begins to disappear. Some of the strategies used to convert peptides to peptidomimetics were recently reviewed,192 while a 2016 study reported on a systematic comparison of the proteolytic resistance imparted by four backbone modifications commonly employed in the design of protease-stable analogues of peptides, in an attempt to create a rational approach to maximise proteolytic stability with minimal unnatural residue content.193 N-methylation is one common approach that introduces conformational constraints which can significantly affect ligand potency and receptor subtype selectivity.194 A peptide to peptidomimetic transformation is nicely illustrated in a recent paper from Novartis (Scheme 26), in which a tripeptide-like diacylglycerol acyltransferases (DGAT1) inhibitor 241 (DGAT1 IC50 = 0.007 µM, but not bioavailable or efficacious when dosed orally to rats) was first Cterminal modified (242), then N-terminal modified (243), then further derivatised to produce 52 ACS Paragon Plus Environment

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244, with IC50 = 0.062 µM, improved solubility, gut permeability and metabolic stability, high oral bioavailability (76%), and oral efficacy (Scheme 9).195 Attempts to remove the central amino acid residue produced an inactive compound 245. Scheme 26. Peptide to Peptidomimetic Conversion



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HCV protease inhibitors for treatment of HCV infections, are a particularly fertile ground for a range of highly modified peptides, with a number of large pharmaceutical companies ending up with very similar motifs consisting predominantly, or entirely, of highly modified unusual amino acids (Schemes 27, 28). Boceprevir 246 (SCH 503034) is a tripeptide with an N-terminal Boc-tert-Leu (tLeu), a central bicyclic proline derivative, and C-teminal cyclobutylalanine α-ketoamide analogue.196 Telaprevir 247 (Incivek, VX-950) is a similar tetrapeptide, but with N-terminal pyrazine acyl group, followed by Chg, a different bicyclic Pro, then a norvaline-derived α-keto cyclopropylamide.197 In contrast, faldaprevir 248 (BI 201335)198 (abandoned after reaching Phase III) and asunaaprevir 249 (BMS-650032)199 (still in Phase III trials) both retain an N-terminal Tle, but use a C-terminal 1-amino-2-vinylcyclopropyl-1-carboxylic acid residue and a hydroxyproline residue O-arylated with a substituted quinolone group. 251 (BMS-605339) has a similar structure, with a publication describing its derivation from hexapeptide Ac-Asp-GluNva-Ile-Cha-Cys-OH 250.200 The progression of a similar peptide lead, H-Asp-Asp-Ile-ProCys-OH, to faldaprevir 248 and ciluprevir 254 has also been discussed.201 An excellent example of the number of potential approaches to a complex unusual amino acid was recently reported for vinyl-ACC, a component of the HCV proteases inhibibtors.202

Scheme 27. Unusual Amino Acids in HCV Protease Inhibitor Peptidomimetics


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The Tle residue has been removed from these structures by cyclizing the end of the vinyl substituent on the 1-aminocyclopropyl-1-carboxylic acid residue to the side chain of the amino acid acylating the N-terminus of the heteroaryloxy-Pro residue, leading to danoprevir 253 (ITMN-191/R7227) (e.g from 252),203 ciluprevir 254 (BILN 2061),204,205 and an analogue of faldaprevir designed to retain activity against resistant strains 255.206 Alternatively, the hydroxyPro residue has been replaced with a cyclopentane-1,2-dicarboxylic acid residue in 256, which again was cyclized to the vinyl-ACC residue to give simeprevir 257 (TMC435) (Scheme 28).207 The hydroxy-Pro residue has also been replaced with an Oarylated homoserine residue in 258,208 or with a ring-expanded hydroxypipecolic acid residue in 261 (IDX320)209, which was derived from a series of different ring sizes in 259 and 260. In contrast, vaniprevir 262 (MK-7009)210 and 263 (MK-5172)211 cyclize the N-terminus of the Tle residue to the hydroxyPro O-aryl substituent, rather than the C-terminal cyclopropyl amino acid. Hundreds, if not thousands of other complex related structures have been reported in the references cited above, and many other publications and patents. Cyclic peptidomimetics for other indications have been developed (Scheme 29). Atanavir 264212 is an HIV protease inhibitor possessing a central dipeptide isostere core symmetrically substituted on either end with a Tle residue. Cobicistat 265 (GS-9350) 213 is a potent, and selective inhibitor of human cytochrome P450 3A that acts as a pharmacoenhancer, boosting plasma concentrations of other HIV drugs. It also has a central dipeptide isostere core, but with a 2-amino-4-(4-morpholinyl) butanoic acid residue and symmetrical thiazole capping groups. 56 ACS Paragon Plus Environment

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Scheme 28. Unusual Amino Acids in HCV Protease Inhibitor Peptidomimetics (cont.)

Other peptidomimetic protease inhibitors include the HIV protease inhibitor indinavir 266 (Crixivan, L-735,524) which contains an N-alkylated piperazine-2-carboxylic acid residue.214 Saquinavir 267 (Fortovase, Ro 31-8959), contains a hydroxyethylamine isostere



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core unit consisting of an N-alkylated decahydroisoquinoline-3-carboxylic acid, fully reduced Tic.215

Scheme 29. Unusual Amino Acids in Peptidomimetics

Cyclised pentapeptide 268, with a glycosyl amino acid, constrained cyclic amino acid, dimethyl-Tyr and ethyl-bridged Cys/penicillamine residues, shows the diversity of unusual 58 ACS Paragon Plus Environment

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amino acids that can be included in one compound; it displayed µ opioid receptor (MOPr) agonist and δ opioid receptor (DOPr) antagonist activity and in vivo activity.216 The most simple homoarylalanine, homophenylalanine, is a component of enalapril (Vasotec, Epaned) 269, a tripeptide-like angiotensin-converting enzyme (ACE) inhibitor.217 Hfe is also contained in lisinopril (Zestril, Prinivil) 270, the third ACE inhibitor introduced (after captopril and enalapril),218 and in carfilzomib (Kyprolis) 271, a proteasome inhibitor used to treat cancer. The tetrapeptide epoxyketone was derived from the natural product epoxomicin.219

2.8. Unusual Amino Acids in Small Molecules. Some amino acids are so intrinsically incorporated into small molecule drugs and naural products that it is difficult to notice their presence (Scheme 30). Inhibitors of tryptophan hydroxylase-1 (TPH1), involved in the production of the neurotransmitter serotonin, are of interest for a range of indications. Lexicon Pharmaceuticals has developed telotristat etiprate 272, an orally bioavailable ester prodrug of the TPH1 inhibitor 273 (LX1033), which is currently in Phase III clinical trials for the treatment of gastrointestinal symptoms associated with carcinoid syndrome.220 The drug is essentially an aryl–substitututed Phe derivative. Karos Pharmaceuticals has modified the ‘Phe’-like amino acid to a spirocyclic proline derivative to give 274, with similar enzymatic potency.221 Waltherine-C 275 is a 14-membered cyclopeptide alkaloid from the dried powdered bark of the Waltheria douradinha tree of Brazil (20 mg from 2.8 kg of bark). This plant is used in traditional folk medicine to wash wounds, combat laryngitis and as a bronchial anti-inflammatory agent,222 and is based around an O59 ACS Paragon Plus Environment


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aryl β-hydroxy-Leu core. Pipecolic acid is contained in the macrolides rapamycin (sirolimus, Rapamune) 276 and everolimus (Afinitor, Zortress, Certican) 277, used to prevent rejection in organ transplantation, and in oncology. Scheme 30. Unusual Amino Acids in Small Molecules


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3. CONCLUSIONS AND FUTURE PROSPECTS Amino acids are an indispensable component of the modern medicinal chemist’s repertoire. More and more unusual amino acids are becoming commercially available at reasonable prices, providing further incentive for their incorporation into drug discovery SAR, hit to lead, and lead optimisation programs. This perspective aimed to provide an overview of the array of functionality presented by unusual amino acids, and provide inspiration to medicinal chemists who may not have been fully aware of either their diversity or their ability to improve the potency, selectivity and/or ADMET properties of drugs. Amino acids provide a number of features desirable for new drug discovery and development. Their inclusion in compounds improves both compound complexity (as measured by the fraction of sp3 centers, Fsp3, which = number of sp3 hybridized carbons/total carbon count) and chiral count (whether a chiral carbon exists in the molecule), with both criteria correlating with success as compounds move from discovery through to approval (64% of approved drugs have one or more stereocenters, compared to 53% of discovery compounds).228 Promiscuity and off-target toxicity are reduced with increased Fsp3 and number of chiral centers (48% decrease in promiscuity for non-aminergic compounds and 59% for aminergic compounds when number of chiral centers increases from n = 0 to n > 2).1 Furthermore, the amine and carboxyl functional groups provided by amino acids are readily derivatised by the types of reactions commonly employed by medicinal chemists, who tend to rely on a few key reactions (top 10 reaction types account for 60-90% of reactions).229,230 In one study, the reactions generally used to incorporate/functionalise amino acids (amide and sulfonamide condensations and alkylations) accounted for 34% of all reactions,229 while 61 ACS Paragon Plus Environment


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in a larger study the acylation (22%) and N-alkylation/arylation (18%) reactions comprised 40% of the total.230 Amino acids are unique building blocks in that they are found in all three major classes of drug – small molecules, peptides and proteins. As such, no matter what the trend in direction for future drugs (i.e. the shift to biological drugs over the past two decades), amino acids will remain in demand. As outlined by Craik et al.,3 the identification of new protein targets by genomics/proteomics focus attention on protein–protein interactions as targets for drug design, requiring a greater emphasis on peptides or proteins as prospective drugs that are able to successfully interact with large surface areas. Futhermore, the trend to personalized therapies will lead to the need for more selective target specificity (i.e. for receptor subtypes or mutated targets), again favouring peptide and protein drugs, with unusual amino acids assisting in tailoring their specificity. There is currently a gap in the size of approved drugs between conventional small molecules (MW5000 Da), which is increasingly being filled by peptides with 5-50 residues.3 Peptide/protein drugs held a growing 10% of the pharmaceutical market share (>$40 billion per year) in 2013, with drug pipeline success rates twice that of small molecule drugs.3 A 2015 review estimated that more than 60 approved peptide medicines are on the market, 140 in clinical trials and more than 500 in preclinical development, with global peptide drug sales predicted to increase from US$14.1 billion in 2011 to US$25.4 billion in 2018.2 There are significant research efforts underway to improve the understanding on how to make better peptide drugs, focusing on enhancing their membrane permeability, reducing microsomal and proteolytic metabolism, and reducing their often high clearance rates. For 62 ACS Paragon Plus Environment

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example, recent studies have proposed general principles to improve peptide stability, potency and oral bioavailability by steric inhibition,129 cyclisation,90 N-methylation3,231 and cyclic peptide scaffold design.232 Unusual amino acids play a key role in all of these potential modifications. These advancements augur a future where rapid engineering and rational design are able to produce the next generation of peptide-based drug leads, relying extensively on the modular building blocks provided by an increasing large pool of available unusual amino acids.



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ABBREVIATIONS α-aminoisobutyric acid (Aib), 1-amino-2-phenylcyclopropane-1-carboxylic acid (2,3methano-Phe, 2-Ph-ACC), 2,3-diaminobutyric acid (DABA), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab, 2,6-diaminopimelic acid (DAP, 2-amino-2-(3hydroxy-5-methylisoxazol-4-yl)acetic acid (AMMA), 2-amino-3-(3-hydroxy-5methylisoxazol-4-yl)propionic acid (AMPA), 2-aminobutyric acid (Abu), 2azabicyclo[3.3.0]octane-3-carboxylic acid (Aoc), 3,4-dihydroxyphenylalanine (Dopa), 4’phosphonodifluoromethyl-Phe (F2Pmp), 4’-phosphonomethyl-Phe (Pmp), adamantylglycine (Adg), adrenocorticotropic hormone (ACTH), angiotensin-converting enzyme (ACE), boron neutron capture therapy (BNCT), central nervous system (CNS), cyclohexylalanine (Cha), cyclohexylglycine (Chg), cyclopropylalanine (Cpa), cyclosporine A (CsA), diacylglycerol acyltransferases (DGAT1), follicle-stimulating hormone–releasing hormone (FSH-RH), free fatty acid receptor 2 (FFA2), glucagon-like peptide-1 (GLP-1), gonadotropin-releasing hormone (GnRH), integrin leukocyte function associated antigen 1 (LFA-1), Janus tyrosine kinase 3 (JAK3), luteinizing hormone–releasing hormone (LHRH), nicotinic acetylcholine receptor (nAChR), N-Methyl-D-aspartic acid (NMDA), norleucine (Nle), norvaline (Nva), octahydroindole-2-carboxylic acid (Oic), O-fluoromalonyl Tyr (FOMT), O-malonyl Tyr (OMT), ornithine (Orn), p-boronophenylalanine (BPA), phenylglycine (Phg), phenylglycine (Phg), phospho-Tyr (pTyr), protein tyrosine phosphatase 1B (PTP-1B), tert-butylalanine (Tba), tert-leucine (Tle), tetrahydro-isoquinoline-3-carboxylic acid (Tic), tryptophan hydroxylase-1 (TPH1).


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Phone +61-7-3346-2994.

Conflict of Interest MATB is an inventor on a number of patents relating to drugs incorporating unusual amino acids and receives royalties from a book on amino acid synthesis.

Biographical Sketch Dr Mark Blaskovich is a Senior Research Chemist at the Institute for Molecular Bioscience at the University of Queensland, and Program Coordinator for the Community for Open Antimicrobial Drug Discovery. He gained his fascination with unusual amino acids during his PhD, developing a useful route to functionalise the side chain of serine. His thesis introduction evolved into the comprehensive ‘Handbook on Syntheses of Amino Acids”. Mark’s appreciation of unusual amino acids in medicinal chemistry was forged during a career at three peptidomimetic-based biotech companies, driven by drug discovery efforts targeting coagulation protease inhibitors (Arg analogs), GPCR ligands (Arg and Trp analogs) and PTP1B inhibitors (phospho-Tyr analogs). He is now focused on peptide and glycopeptide antibiotics, still relying on the incredible diversity of unusual amino acids.



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REFERENCES 1.

Lovering, F. Escape from flatland 2: Complexity and promiscuity. MedChemComm 2013, 4, 515-519.

2.

Fosgerau, K.; Hoffmann, T. Peptide therapeutics: Current status and future directions. Drug Disc. Today Targets 2015, 20, 122-128.

3.

Craik, D. J.; Fairlie, D. P.; Liras, S.; Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des. 2013, 81, 136-147.

4.

Bock, A.; Forchhammer, K.; Heider, J.; Leinfelder, W.; Sawers, G.; Veprek, B.; Zinoni, F. Selenocysteine: The 21st amino acid. Mol. Microbiol. 1991, 5, 515-520.

5.

Hao, B.; Gong, W.; Ferguson, T. K.; James, C. M.; Krzycki, J. A.; Chan, M. K. A new UAGencoded residue in the structure of a methanogen methyltransferase. Science 2002, 296, 14621466.

6.

Hardy, P. M. The protein amino acids. In Chemistry and biochemistry of the amino acids, Barrett, G. C., Ed. Chapman and Hall: New York, 1985; pp 6-24.

7.

Hunt, S. The non-protein amino acids. In Chemistry and biochemistry of the amino acids, Barrett, G. C., Ed. Chapman and Hall: New York, 1985; pp 55-138.

8.

Blaskovich, M. A. Handbook on syntheses of amino acids : General routes for the syntheses of amino acids. Oxford University Press: Oxford; New York, 2010; 1305 pp.

9.

Stevenazzi, A.; Marchini, M.; Sandrone, G.; Vergani, B.; Lattanzio, M. Amino acidic scaffolds bearing unnatural side chains: An old idea generates new and versatile tools for the life sciences. Bioorg. Med. Chem. Lett. 2014, 24, 5349-5356.

10.

Watkins, J. C.; Olverman, H. J. Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci. 10, 265-272.


Page 67 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

11.


Patil, S. T.; Zhang, L.; Martenyi, F.; Lowe, S. L.; Jackson, K. A.; Andreev, B. V.; Avedisova, A. S.; Bardenstein, L. M.; Gurovich, I. Y.; Morozova, M. A.; Mosolov, S. N.; Neznanov, N. G.; Reznik, A. M.; Smulevich, A. B.; Tochilov, V. A.; Johnson, B. G.; Monn, J. A.; Schoepp, D. D. Activation of mglu2/3 receptors as a new approach to treat schizophrenia: A randomized phase 2 clinical trial. Nat. Med. 2007, 13, 1102-1107.

12.

Monn, J. A.; Valli, M. J.; Massey, S. M.; Hao, J.; Reinhard, M. R.; Bures, M. G.; Heinz, B. A.; Wang, X.; Carter, J. H.; Getman, B. G.; Stephenson, G. A.; Herin, M.; Catlow, J. T.; Swanson, S.; Johnson, B. G.; McKinzie, D. L.; Henry, S. S. Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: Identification of new potent and selective metabotropic glutamate 2/3 receptor agonists. J. Med.Chem. 2013, 56, 4442-4455.

13.

Monn, J. A.; Prieto, L.; Taboada, L.; Pedregal, C.; Hao, J.; Reinhard, M. R.; Henry, S. S.; Goldsmith, P. J.; Beadle, C. D.; Walton, L.; Man, T.; Rudyk, H.; Clark, B.; Tupper, D.; Baker, S. R.; Lamas, C.; Montero, C.; Marcos, A.; Blanco, J.; Bures, M.; Clawson, D. K.; Atwell, S.; Lu, F.; Wang, J.; Russell, M.; Heinz, B. A.; Wang, X.; Carter, J. H.; Xiang, C.; Catlow, J. T.; Swanson, S.; Sanger, H.; Broad, L. M.; Johnson, M. P.; Knopp, K. L.; Simmons, R. M.; Johnson, B. G.; Shaw, D. B.; McKinzie, D. L. Synthesis and pharmacological characterization of C4-disubstituted analogs of 1s,2s,5r,6s-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mglu2 and mglu3 amino terminal domain structures. J. Med.Chem. 2015, 58, 1776-1794.

14.

Zhang, F.; Song, Z. J.; Tschaen, D.; Volante, R. P. Enantioselective preparation of ring-fused 1fluorocyclopropane-1-carboxylate derivatives: En route to mglur 2 receptor agonist mgs0028. Org. Lett. 2004, 6, 3775-3777.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

15.

Page 68 of 96

Gu, Z.-Q.; Hesson, D. P.; Pelletier, J. C.; Maccecchini, M.-L.; Zhou, L.-M.; Skolnick, P. Synthesis, resolution, and biological evaluation of the four stereoisomers of 4-methylglutamic acid: Selective probes of kainate receptors. J. Med. Chem. 1995, 38, 2518-2520.

16.

Pellicciari, R.; Marinozzi, M.; Natalini, B.; Costantino, G.; Luneia, R.; Giorgi, G.; Moroni, F.; Thomsen, C. Synthesis and pharmacological characterization of all sixteen stereoisomers of 2(2‘-carboxy-3‘-phenylcyclopropyl)glycine. Focus on (2s,1‘s,2‘s,3‘r)-2-(2‘-carboxy-3‘phenylcyclopropyl)glycine, a novel and selective group II metabotropic glutamate receptors antagonist. J. Med. Chem. 1996, 39, 2259-2269.

17.

Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Wright, R. A.; Johnson, B. G.; Schoepp, D. D. 2substituted (2sr)-2-amino-2-((1sr,2sr)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group ii metabotropic glutamate receptors. 1. Effects of alkyl, arylalkyl, and diarylalkyl substitution. J. Med. Chem. 1998, 41, 346-357.

18.

Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Kennedy, J. H.; Wright, R. A.; Johnson, B. G.; Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp, D. D.; Hérin, M. 2-substituted (2sr)-2amino-2-((1sr,2sr)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group ii metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. J. Med. Chem. 1998, 41, 358-378.

19.

Dardenne, G. A.; Casimir, J.; Bell, E. A.; Nulu, J. R. Two stereoisomers of β-hydroxy-γ-methylglutamic acid from seeds of gymnocladus dioicus. Phytochem. 1972, 11, 787-790.

20.

Christensen, S. B.; Krogsgaard-Larsen, P. Structural analogues of ibotenic acid. Synthesis of (+)-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid and derivatives thereof. Acta Chem. Scand. B 1978, 32, 27-30.

21.

Bräuner-Osborne, H.; Sløk, F. A.; Skjærbæk, N.; Ebert, B.; Sekiyama, N.; Nakanishi, S.; Krogsgaard-Larsen, P. A new highly selective metabotropic excitatory amino acid agonist: 2amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid. J. Med. Chem. 1996, 39, 3188-3194. 68 ACS Paragon Plus Environment

Page 69 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

22.


Farthing, C. N.; Baldwin, J. E.; Russell, A. T.; Schofield, C. J.; Spivey, A. C. Syntheses of (s)-βpyrazolylalanine and (s)-quisqualic acid from a serine-derived aziridine. Tetrahedron Lett. 1996, 37, 5225-5226.

23.

Kozikowski, A. P.; Steensma, D.; Varasi, M.; Pshenichkin, S.; Surina, E.; Wroblewski, J. T. Αsubstituted quisqualic acid analogs: New metabotropic glutamate receptor group II selective antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 447-452.

24.

Andersson, E.; Hedman, E.; Enander, J.; Radu Djurfeldt, D.; Ljótsson, B.; Cervenka, S.; Isung, J.; Svanborg, C.; Mataix-Cols, D.; Kaldo, V.; Andersson, G.; Lindefors, N.; Rück, C. Dcycloserine vs placebo as adjunct to cognitive behavioral therapy for obsessive-compulsive disorder and interaction with antidepressants: A randomized clinical trial. JAMA Psychiatry 2015, 72, 659-667.

25.

Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Asymmetric synthesis of cis-(−)-(2r4s)-4(phosphonomethyl)-2-piperidinecarboxylic acid, a potent NMDA receptor antagonist. Bioorg. Med. Chem. Lett. 1996, 6, 963-966.

26.

Lloyd, K. G.; Davidson, L.; Hornykiewicz, O. The neurochemistry of parkinson's disease: Effect of L-Dopa therapy. J. Pharmacol. Exp. Ther. 1975, 195, 453-464.

27.

Knowles, W. S. Asymmetric hydrogenations (Nobel lecture). Angew. Chem. Int. Ed. Engl. 2002, 41, 1999-2007.

28.

Mandel, S. J.; Brent, G. A.; Larsen, P. R. Levothyroxine therapy in patients with thyroid disease. Ann. Int. Med. 1993, 119, 492-502.

29.

Coleman, M. W. Determination of the enantiomeric purity of oxfenicine by high-performance liquid chromatography. Chromatographia 17, 23-26.

30.

Larden, D. W.; Cheung, H. T. A. Synthesis of N-α-aminoacyl derivatives of melphalan for potential use in drug targeting. Tetrahedron Lett. 1996, 37, 7581-7582.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

31.

Page 70 of 96

Kleemann, A. L., W.; Hoppe, B.; Tanner, H. Ullmann's encyclopedia of industrial chemistry. 5th, completely rev. ed.; VCH: Weinheim, Federal Republic of Germany ; Deerfield Beach, FL, USA, 1985; Vol. A2, p 57-97.

32.

Greenstein, J. P.; Winitz, M. Chemistry of the amino acids. Wiley: New York,, 1961; Vol. 3.

33.

Amer, A.; Breu, J.; McDermott, J.; Wurtman, R. J.; Maher, T. J. 5-hydroxy-L-tryptophan suppresses food intake in food-deprived and stressed rats. Pharmacol. Biochem. Behav. 2004, 77, 137-143.

34.

Crounse, R. G.; Maxwell, J. D.; Blank, H. Inhibition of growth of hair by mimosine. Nature 1962, 194, 694-695.

35.

Wallace, G. C.; Fukuto, J. M. Synthesis and bioactivity of n.Omega.-hydroxyarginine: A possible intermediate in the biosynthesis of nitric oxide from arginine. J. Med. Chem. 1991, 34, 1746-1748.

36.

Marletta, M. A. Approaches toward selective inhibition of nitric oxide synthase. J. Med. Chem. 1994, 37, 1899-1907.

37.

Ho, B.; Zabriskie, T. M. Epoxide derivatives of pipecolic acid and proline are inhibitors of pipecolate oxidase. Bioorg. Med. Chem. Lett. 1998, 8, 739-744.

38.

Cox, P. A.; Banack, S. A.; Murch, S. J.; Rasmussen, U.; Tien, G.; Bidigare, R. R.; Metcalf, J. S.; Morrison, L. F.; Codd, G. A.; Bergman, B. Diverse taxa of cyanobacteria produce β-Nmethylamino-L-alanine, a neurotoxic amino acid. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 50745078.

39.

Rando, R. R. Irreversible inhibition of aspartate aminotransferase by 2-amino-3-butenoic acid. Biochem. 1974, 13, 3859-3863.

40.

Lacoste, A. M.; Darriet, M.; Neuzil, E.; Legoffic, F. Inhibition of alanine racemase by vinylglycine and its phosphonic analog - a H-1 nuclear magnetic-resonance spectroscopy study. Biochem. Soc. Trans. 1988, 16, 606-608. 70 ACS Paragon Plus Environment

Page 71 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

41.


Relyea, N.; Rando, R. R. Potent inhibition of ornithine decarboxylase by β, γ unsaturated substrate analogs. Biochem. Biophys. Res. Commun. 1975, 67, 392-402.

42.

Bey, P.; Vevert, J. P. Stereospecific alkylation of the Schiff base ester of alanine with 2substituted-(e)- and -(z)-vinyl bromides. An efficient synthesis of 2-methyl-(e)-3,4didehydroglutamic acid, a potent substrate-induced irreversible inhibitor of l-glutamate-1decarboxylase. J. Org. Chem. 1980, 45, 3249-3253.

43.

Dittmer, K.; Goering, H. L.; Goodman, I.; Cristol, S. J. The inhibition of microbiological growth by allylglycine, methallylglycine and crotylglycine. J. Am. Chem. Soc. 1948, 70, 2499-2501.

44.

De Ropp, R. S.; Van Meter, J. C.; De Renzo, E. C.; McKerns, K. W.; Pidacks, C.; Bell, P. H.; Ullman, E. F.; Safir, S. R.; Fanshawe, W. J.; Davis, S. B. The structure and biological activities of hypoglycin. J. Am. Chem. Soc. 1958, 80, 1004-1005.

45.

Hassall, C. H.; Reyle, K.; Feng, P. Hypoglycin a,b: Biologically active polypeptides from blighia sapida. Nature 1954, 173, 356-357.

46.

Yarnell, A. More than just sun and sand. Chemical & Engineering News Archive 2004, 82, 3134.

47.

Walsh, C. Suicide substrates: Mechanism-based enzyme inactivators. Tetrahedron 1982, 38, 871-909.

48.

Silverman, R. B.; Abeles, R. H. Mechanism of inactivation of γ-cystathionase by β,β,βtrifluoroalanine. Biochem. 1977, 16, 5515-5520.

49.

Wang, E.; Walsh, C. Suicide substrates for the alanine racemase of escherichia coli b. Biochem. 1978, 17, 1313-1321.

50.

Katagiri, K.; Tori, K.; Kimura, Y.; Yoshida, T.; Nagasaki, T.; Minato, H. A new antibiotic. Furanomycin, an isoleucine antagonist. J. Med. Chem. 1967, 10, 1149-1154.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

51.

Page 72 of 96

Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. Practical asymmetric syntheses of .Alpha.amino acids through carbon-carbon bond constructions on electrophilic glycine templates. J. Am. Chem. Soc. 1988, 110, 1547-1557.

52.

Curphey, T. J.; Daniel, D. S. New synthesis of azaserine. J. Org. Chem. 1978, 43, 4666-4668.

53.

Schow, S. R.; DeJoy, S. Q.; Wick, M. M.; Kerwar, S. S. Diastereoselective synthesis of the antibiotic L-azatyrosine. J. Org. Chem. 1994, 59, 6850-6852.

54.

Kindler, H. L.; Burris, H. A.; Sandler, A. B.; Oliff, I. A. A phase II multicenter study of Lalanosine, a potent inhibitor of adenine biosynthesis, in patients with mtap-deficient cancer. Investigational New Drugs 2008, 27, 75-81.

55.

Bolster, J. M. V., W.; Elsinga, Ph. H.; Ishiwata, K.; Vissering, H.; Woldring, M.G. . The preparation of 11C-carboxylic labelled L-methionine for measuring protein sysnthesis rates. Sixth international symposium on radiopharmaceutical chemistry. Abstracts. J. Lab. Comp. Radiopharm. 1986, 23, 1081-1082.

56.

Garnett, E. S.; Firnau, G.; Nahmias, C. Dopamine visualized in the basal ganglia of living man. Nature 1983, 305, 137-138.

57.

Iwata, R.; Furumoto, S.; Pascali, C.; Bogni, A.; Ishiwata, K. Radiosynthesis of o-[11C]methylL-tyrosine and o-[18F]fluoromethyl-L-tyrosine as potential PET tracers for imaging amino acid transport. J. Lab. Comp. Radiopharm. 2003, 46, 555-566.

58.

Kahl, S. B.; Kasar, R. A. Simple, high-yield synthesis of polyhedral carborane amino acids. J. Am. Chem. Soc. 1996, 118, 1223-1224.

59.

Mishima, Y.; Honda, C.; Ichihashi, M.; Obara, H.; Hiratsuka, J.; Fukuda, H.; Karashima, H.; Kobayashi, T.; Kanda, K.; Yoshino, K. Treatment of malignant melanoma by single thermal neutron capture therapy with melanoma-seeking 10B-compound. Lancet 1989, 334, 388-389.


Page 73 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

60.


Yong, J. H.; Barth, R. F.; Wyzlic, I. M.; Soloway, A. H.; Rotaru, J. H. In vitro and in vivo evaluation of o-carboranylalanine as a potential boron delivery agent for neutron capture therapy. Anticancer Res. 1995, 15, 2033-2038.

61.

Hamada, T.; Sugawara, T.; Matsunaga, S.; Fusetani, N. Polytheonamides, unprecedented highly cytotoxic polypeptides from the marine sponge theonella swinhoei 2. Structure elucidation. Tetrahedron Lett. 1994, 35, 609-612.

62.

Soth, M.; Hermann, J. C.; Yee, C.; Alam, M.; Barnett, J. W.; Berry, P.; Browner, M. F.; Frank, K.; Frauchiger, S.; Harris, S.; He, Y.; Hekmat-Nejad, M.; Hendricks, T.; Henningsen, R.; Hilgenkamp, R.; Ho, H.; Hoffman, A.; Hsu, P. Y.; Hu, D. Q.; Itano, A.; Jaime-Figueroa, S.; Jahangir, A.; Jin, S.; Kuglstatter, A.; Kutach, A. K.; Liao, C.; Lynch, S.; Menke, J.; Niu, L.; Patel, V.; Railkar, A.; Roy, D.; Shao, A.; Shaw, D.; Steiner, S.; Sun, Y.; Tan, S. L.; Wang, S.; Vu, M. D. 3-amido pyrrolopyrazine jak kinase inhibitors: Development of a jak3 vs jak1 selective inhibitor and evaluation in cellular and in vivo models. J. Med.Chem. 2013, 56, 345356.

63.

Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase iv inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 5025-5037.

64.

Curreli, F.; Haque, K.; Xie, L.; Qiu, Q.; Xu, J.; Yong, W.; Tong, X.; Debnath, A. K. Synthesis, antiviral activity and resistance of a novel small molecule hiv-1 entry inhibitor. Bioorg. Med. Chem. 2015, 23, 7618-7628.

65.

Civiello, R. L.; Han, X.; Beno, B. R.; Chaturvedula, P. V.; Herbst, J. J.; Xu, C.; Conway, C. M.; Macor, J. E.; Dubowchik, G. M. Synthesis and SAR of calcitonin gene-related peptide (cgrp) 73 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 74 of 96

antagonists containing substituted aryl-piperazines and piperidines. Bioorg. Med. Chem. Lett. 2016, 26, 1229-1232. 66.

Perucca, E.; Yasothan, U.; Clincke, G.; Kirkpatrick, P. Lacosamide. Nat. Rev. Drug. Discov. 2008, 7, 973-974.

67.

Durand, P.; Richard, P.; Renaut, P. (−)-15-deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J. Org. Chem. 1998, 63, 9723-9727.

68.

Caroff, E.; Hubler, F.; Meyer, E.; Renneberg, D.; Gnerre, C.; Treiber, A.; Rey, M.; Hess, P.; Steiner, B.; Hilpert, K.; Riederer, M. A. 4-((r)-2-{[6-((s)-3-methoxypyrrolidin-1-yl)-2phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid butyl ester (act-246475) and its prodrug (act-281959), a novel p2y12 receptor antagonist with a wider therapeutic window in the rat than clopidogrel. J. Med. Chem. 2015, 58, 9133-9153.

69.

Burlacu, C. L.; Buggy, D. J. Update on local anesthetics: Focus on levobupivacaine. Ther. Clin. Risk Man. 2008, 4, 381-392.

70.

Bruce, M. A.; St. Laurent, D. R.; Poindexter, G. S.; Monkovic, I.; Huang, S.; Balasubramanian, N. Kinetic resolution of piperazine-2-carboxamide by leucine aminopeptidase. An application in the synthesis of the nucleoside transport blocker (-) draflazine. Synth. Commun. 1995, 25, 26732684.

71.

Shentu, X.; Liu, N.; Tang, G.; Tanaka, Y.; Ochi, K.; Xu, J.; Yu, X. Improved antibiotic production and silent gene activation in streptomyces diastatochromogenes by ribosome engineering. J. Antibiot. 2016, 69, 406-410.

72.

Birkenmeyer, R. D.; Kroll, S. J.; Lewis, C.; Stern, K. F.; Zurenko, G. E. Synthesis and antimicrobial activity of clindamycin analogs: Pirlimycin, a potent antibacterial agent. J. Med. Chem. 1984, 27, 216-223.


Page 75 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

73.


Encinas, L.; O'Keefe, H.; Neu, M.; Remuinan, M. J.; Patel, A. M.; Guardia, A.; Davie, C. P.; Perez-Macias, N.; Yang, H.; Convery, M. A.; Messer, J. A.; Perez-Herran, E.; Centrella, P. A.; Alvarez-Gomez, D.; Clark, M. A.; Huss, S.; O'Donovan, G. K.; Ortega-Muro, F.; McDowell, W.; Castaneda, P.; Arico-Muendel, C. C.; Pajk, S.; Rullas, J.; Angulo-Barturen, I.; Alvarez-Ruiz, E.; Mendoza-Losana, A.; Ballell Pages, L.; Castro-Pichel, J.; Evindar, G. Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of mycobacterium tuberculosis inha. J. Med.Chem. 2014, 57, 1276-1288.

74.

Phillips, D. P.; Gao, W.; Yang, Y.; Zhang, G.; Lerario, I. K.; Lau, T. L.; Jiang, J.; Wang, X.; Nguyen, D. G.; Bhat, B. G.; Trotter, C.; Sullivan, H.; Welzel, G.; Landry, J.; Chen, Y.; Joseph, S. B.; Li, C.; Gordon, W. P.; Richmond, W.; Johnson, K.; Bretz, A.; Bursulaya, B.; Pan, S.; McNamara, P.; Seidel, H. M. Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2carboxamides as potent, orally bioavailable tgr5 (gpbar1) agonists: Structure-activity relationships, lead optimization, and chronic in vivo efficacy. J. Med.Chem. 2014, 57, 32633282.

75.

San Sebastian, E.; Zimmerman, T.; Zubia, A.; Vara, Y.; Martin, E.; Sirockin, F.; Dejaegere, A.; Stote, R. H.; Lopez, X.; Pantoja-Uceda, D.; Valcarcel, M.; Mendoza, L.; Vidal-Vanaclocha, F.; Cossio, F. P.; Blanco, F. J. Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development. J. Med.Chem. 2013, 56, 735-747.

76.

Farmer, L. J.; Ledeboer, M. W.; Hoock, T.; Arnost, M. J.; Bethiel, R. S.; Bennani, Y. L.; Black, J. J.; Brummel, C. L.; Chakilam, A.; Dorsch, W. A.; Fan, B.; Cochran, J. E.; Halas, S.; Harrington, E. M.; Hogan, J. K.; Howe, D.; Huang, H.; Jacobs, D. H.; Laitinen, L. M.; Liao, S.; Mahajan, S.; Marone, V.; Martinez-Botella, G.; McCarthy, P.; Messersmith, D.; Namchuk, M.; Oh, L.; Penney, M. S.; Pierce, A. C.; Raybuck, S. A.; Rugg, A.; Salituro, F. G.; Saxena, K.; 75 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 76 of 96

Shannon, D.; Shlyakter, D.; Swenson, L.; Tian, S. K.; Town, C.; Wang, J.; Wang, T.; Wannamaker, M. W.; Winquist, R. J.; Zuccola, H. J. Discovery of VX-509 (decernotinib): A potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med.Chem. 2015, 58, 7195-7216. 77.

Beaulieu, P. L.; Bös, M.; Cordingley, M. G.; Chabot, C.; Fazal, G.; Garneau, M.; Gillard, J. R.; Jolicoeur, E.; LaPlante, S.; McKercher, G.; Poirier, M.; Poupart, M.-A.; Tsantrizos, Y. S.; Duan, J.; Kukolj, G. Discovery of the first thumb pocket 1 ns5b polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis c virus (hcv). J. Med. Chem. 2012, 55, 7650-7666.

78.

Furber, M.; Tiden, A. K.; Gardiner, P.; Mete, A.; Ford, R.; Millichip, I.; Stein, L.; Mather, A.; Kinchin, E.; Luckhurst, C.; Barber, S.; Cage, P.; Sanganee, H.; Austin, R.; Chohan, K.; Beri, R.; Thong, B.; Wallace, A.; Oreffo, V.; Hutchinson, R.; Harper, S.; Debreczeni, J.; Breed, J.; Wissler, L.; Edman, K. Cathepsin c inhibitors: Property optimization and identification of a clinical candidate. J. Med.Chem. 2014, 57, 2357-2367.

79.

Addie, M.; Ballard, P.; Buttar, D.; Crafter, C.; Currie, G.; Davies, B. R.; Debreczeni, J.; Dry, H.; Dudley, P.; Greenwood, R.; Johnson, P. D.; Kettle, J. G.; Lane, C.; Lamont, G.; Leach, A.; Luke, R. W.; Morris, J.; Ogilvie, D.; Page, K.; Pass, M.; Pearson, S.; Ruston, L. Discovery of 4-aminoN-[(1s)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7h-pyrrolo[2,3-d]pyrimidin -4-yl)piperidine-4carboxamide (AZD5363), an orally bioavailable, potent inhibitor of akt kinases. J. Med.Chem. 2013, 56, 2059-2073.

80.

Feldman, P. L.; Brackeen, M. F. A novel route to the 4-anilido-4-(methoxycarbonyl)piperidine class of analgetics. J. Org. Chem. 1990, 55, 4207-4209.

81.

Coleman, M. J.; Goodyear, M. D.; Latham, D. W. S.; Whitehead, A. J. A convenient method for the N-acylation and esterification of hindered amino acids: Synthesis of ultra short acting opioid agonist, remifentanil. Synlett 1999, 1923-1924. 76 ACS Paragon Plus Environment

Page 77 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

82.


Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman, M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.; Discenza, L.; Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson, W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.; Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.; Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.; Vyas, D. M. Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (igf-1r) kinase in clinical development. J. Med.Chem. 2009, 52, 7360-7363.

83.

Pizzonero, M.; Dupont, S.; Babel, M.; Beaumont, S.; Bienvenu, N.; Blanqué, R.; Cherel, L.; Christophe, T.; Crescenzi, B.; De Lemos, E.; Delerive, P.; Deprez, P.; De Vos, S.; Djata, F.; Fletcher, S.; Kopiejewski, S.; L’Ebraly, C.; Lefrançois, J.-M.; Lavazais, S.; Manioc, M.; Nelles, L.; Oste, L.; Polancec, D.; Quénéhen, V.; Soulas, F.; Triballeau, N.; van der Aar, E. M.; Vandeghinste, N.; Wakselman, E.; Brys, R.; Saniere, L. Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: From hit to clinic. J. Med. Chem. 2014, 57, 10044-10057.

84.

Hill, T. A.; Shepherd, N. E.; Diness, F.; Fairlie, D. P. Constraining cyclic peptides to mimic protein structure motifs. Angew. Chem. Int. Ed. Engl. 2014, 53, 13020-13041.

85.

Kyriakakis, N.; Chau, V.; Lynch, J.; Orme, S. M.; Murray, R. D. Lanreotide autogel in acromegaly - a decade on. Expert Opin. Pharmacother. 2014, 15, 2681-2692.

86.

Feelders, R. A.; Yasothan, U.; Kirkpatrick, P. Pasireotide. Nat. Rev. Drug Discov. 2012, 11, 597598.

87.

Gurk-Turner, C. Quinupristin/dalfopristin: The first available macrolide-lincosamidestreptogramin antibiotic. Proceedings Baylor University Medical Center 2000, 13, 83-86.

88.

Raja, A.; LaBonte, J.; Lebbos, J.; Kirkpatrick, P. Daptomycin. Nat. Rev. Drug. Discov. 2003, 2, 943-944.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

89.

Page 78 of 96

Velkov, T.; Roberts, K. D.; Nation, R. L.; Thompson, P. E.; Li, J. Pharmacology of polymyxins: New insights into an 'old' class of antibiotics. Future Microbiol. 2013, 8, 711-724.

90.

Watanabe, K. Vii. Structure of mikamycin b. J. Antibiotics, Ser. A 1961, 14, 1-13.

91.

Butler, M. S.; Hansford, K. A.; Blaskovich, M. A. T.; Halai, R.; Cooper, M. A. Glycopeptide antibiotics: Back to the future. J. Antibiot. 2014, 67, 631-644.

92.

Evans, D. A.; Weber, A. E. Synthesis of the cyclic hexapeptide echinocandin d. New approaches to the asymmetric synthesis of .beta.-hydroxy .alpha.-amino acids. J. Am. Chem. Soc. 1987, 109, 7151-7157.

93.

Chen, S. C.-A.; Slavin, M. A.; Sorrell, T. C. Echinocandin antifungal drugs in fungal infections. Drugs 2012, 71, 11-41.

94.

Chen, H.; Thomas, M. G.; O'Connor, S. E.; Hubbard, B. K.; Burkart, M. D.; Walsh, C. T. Aminoacyl-S-enzyme intermediates in β-hydroxylations and α,β-desaturations of amino acids in peptide antibiotics. Biochem. 2001, 40, 11651-11659.

95.

Tymiak, A. A.; McCormick, T. J.; Unger, S. E. Structure determination of lysobactin, a macrocyclic peptide lactone antibiotic. J. Org. Chem. 1989, 54, 1149-1157.

96.

Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. Total synthesis of bleomycin a2 and related agents. 1. Synthesis and DNA binding properties of the extended c-terminus: Tripeptide s, tetrapeptide s, pentapeptide s, and related agents. J. Am. Chem. Soc. 1994, 116, 5607-5618.

97.

Kato, K.; Takita, T.; Umezawa, H. Synthesis of cleonine, amino(1-hydroxycyclopropyl)acetic acid, a novel amino acid contained in cleomycin. Tetrahedron Lett. 1980, 21, 4925-4926.

98.

Wenger, R. M. Synthesis of cyclosporine and analogues: Structural requirements for immunosuppressive activity. Angew. Chem. Int. Ed. Engl. 1985, 24, 77-85.

99.

Muttenthaler, M.; Andersson, A.; de Araujo, A. D.; Dekan, Z.; Lewis, R. J.; Alewood, P. F. Modulating oxytocin activity and plasma stability by disulfide bond engineering. J. Med. Chem. 2010, 53, 8585-8596. 78 ACS Paragon Plus Environment

Page 79 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

100.


Fukase, K.; Wakamiya, T.; Shiba, T. Synthetic study on peptide antibiotic nisin. II. The synthesis of ring b. Bull. Chem. Soc. Jpn. 1986, 59, 2505-2508.

101.

Kamalov, M.; Kaur, H.; Brimble, M. A. Intermolecular peptide cross-linking by using diaminodicarboxylic acids. Chem. Eur. J. 2016, 22, 3622-3631.

102.

Bhatnagar, P. K.; Agner, E. K.; Alberts, D.; Arbo, B. E.; Callahan, J. F.; Cuthbertson, A. S.; Engelsen, S. J.; Fjerdingstad, H.; Hartmann, M.; Heerding, D.; Hiebl, J.; Huffman, W. F.; Hysben, M.; King, A. G.; Kremminger, P.; Kwon, C.; LoCastro, S.; Løvhaug, D.; Pelus, L. M.; Petteway, S.; Takata, J. S. Structure−activity relationships of novel hematoregulatory peptides. J. Med. Chem. 1996, 39, 3814-3819.

103.

Mierke, D. F.; Said-Nejad, O. E.; Schiller, P. W.; Goodman, M. Enkephalin analogues containing β-naphthylalanine at the fourth position. Biopolymers 1990, 29, 179-196.

104.

Smith, C. W.; Walter, R.; Moore, S.; Makofske, R. C.; Meienhofer, J. Replacement of the disulfide bond in oxytocin by an amide group. Synthesis and some biological properties of [cyclo-(1-L-aspartic acid, 6-L-.alpha.,.beta.-diaminopropionic acid)]oxytocin. J. Med. Chem. 1978, 21, 117-120.

105.

Al-Obeidi, F.; Castrucci, A. M. d. L.; Hadley, M. E.; Hruby, V. J. Potent and prolonged-acting cyclic lactam analogs of alpha.-melanotropin: Design based on molecular dynamics. J. Med. Chem. 1989, 32, 2555-2561.

106.

Rew, Y.; Shin, D.; Hwang, I.; Boger, D. L. Total synthesis and examination of three key analogues of ramoplanin: A lipoglycodepsipeptide with potent antibiotic activity. J. Am. Chem. Soc. 2004, 126, 1041-1043.

107.

Epstein, L.; Lamport, D. T. A. An intramolecular linkage involving isodityrosine in extensin. Phytochem. 1984, 23, 1241-1246.

108.

Fry, S. C. Isodityrosine, a new cross-linking amino acid from plant cell-wall glycoprotein. Biochem. J. 1982, 204, 449-455. 79 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

109.

Page 80 of 96

Veber, D. F.; Holly, F. W.; Nutt, R. F.; Bergstrand, S. J.; Brady, S. F.; Hisrschmann, R.; Glitzer, M. S.; Saperstein, R. Highly active cyclic and bicyclic somatostatin analogues of reduced ring size. Nature 1979, 280, 512-514.

110.

Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Walchli, M. Theonellamide f. A novel antifungal bicyclic peptide from a marine sponge theonella sp. J. Am. Chem. Soc. 1989, 111, 2582-2588.

111.

Blackwell, H. E.; Sadowsky, J. D.; Howard, R. J.; Sampson, J. N.; Chao, J. A.; Steinmetz, W. E.; O'Leary, D. J.; Grubbs, R. H. Ring-closing metathesis of olefinic peptides: Design, synthesis, and structural characterization of macrocyclic helical peptides. J. Org. Chem. 2001, 66, 52915302.

112.

Schafmeister, C. E.; Po, J.; Verdine, G. L. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J. Am. Chem. Soc. 2000, 122, 58915892.

113.

Long, Y. Q.; Huang, S. X.; Zawahir, Z.; Xu, Z. L.; Li, H.; Sanchez, T. W.; Zhi, Y.; De Houwer, S.; Christ, F.; Debyser, Z.; Neamati, N. Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors. J. Med.Chem. 2013, 56, 5601-5612.

114.

Chhabra, S.; Belgi, A.; Bartels, P.; van Lierop, B. J.; Robinson, S. D.; Kompella, S. N.; Hung, A.; Callaghan, B. P.; Adams, D. J.; Robinson, A. J.; Norton, R. S. Dicarba analogues of αconotoxin RGIa. Structure, stability, and activity at potential pain targets. J. Med. Chem. 2014, 57, 9933-9944.

115.

Seigal, B. A.; Connors, W. H.; Fraley, A.; Borzilleri, R. M.; Carter, P. H.; Emanuel, S. L.; Fargnoli, J.; Kim, K.; Lei, M.; Naglich, J. G.; Pokross, M. E.; Posy, S. L.; Shen, H.; Surti, N.; Talbott, R.; Zhang, Y.; Terrett, N. K. The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity. J. Med.Chem. 2015, 58, 2855-2861.


Page 81 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

116.


Testa, C.; Scrima, M.; Grimaldi, M.; D’Ursi, A. M.; Dirain, M. L.; Lubin-Germain, N.; Singh, A.; Haskell-Luevano, C.; Chorev, M.; Rovero, P.; Papini, A. M. 1,4-disubstituted[1,2,3]triazolyl-containing analogues of mMT-II: Design, synthesis, conformational analysis, and biological activity. J. Med. Chem. 2014, 57, 9424-9434.

117.

Bork, K.; Yasothan, U.; Kirkpatrick, P. Icatibant. Nat. Rev. Drug. Discov. 2008, 7, 801-802.

118.

Deeks, E. D. Histrelin: In advanced prostate cancer. Drugs 2010, 70, 623-630.

119.

Asami, T.; Nishizawa, N.; Matsui, H.; Nishibori, K.; Ishibashi, Y.; Horikoshi, Y.; Nakayama, M.; Matsumoto, S.; Tarui, N.; Yamaguchi, M.; Matsumoto, H.; Ohtaki, T.; Kitada, C. Design, synthesis, and biological evaluation of novel investigational nonapeptide kiss1r agonists with testosterone-suppressive activity. J. Med.Chem. 2013, 56, 8298-8307.

120.

Yang, B. Plenaxis. Discov. Med. 2004, 4, 26-27.

121.

Lorenz, M.; Evers, A.; Wagner, M. Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity. Bioorg. Med. Chem. Lett. 2013, 23, 4011-4018.

122.

Evans, M. C.; Pradhan, A.; Venkatraman, S.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring α,α-disubstituted amino acids. J. Med. Chem. 1999, 42, 1441-1447.

123.

Heard, K. R.; Wu, W.; Li, Y.; Zhao, P.; Woznica, I.; Lai, J. H.; Beinborn, M.; Sanford, D. G.; Dimare, M. T.; Chiluwal, A. K.; Peters, D. E.; Whicher, D.; Sudmeier, J. L.; Bachovchin, W. W. A general method for making peptide therapeutics resistant to serine protease degradation: Application to dipeptidyl peptidase IV substrates. J. Med.Chem. 2013, 56, 8339-8351.

124.

Mapelli, C.; Kimura, H.; Stammer, C. H. Synthesis of four diastereomeric enkephalins incorporating cyclopropyl phenylalanine. Int. J. Pept. Protein. Res. 1986, 28, 347-359.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

125.

Page 82 of 96

Hsieh, K. H.; LaHann, T. R.; Speth, R. C. Topographic probes of angiotensin and receptor: Potent angiotensin II agonist containing diphenylalanine and long-acting antagonists containing biphenylalanine and 2-indan amino acid in position 8. J. Med. Chem. 1989, 32, 898-903.

126.

Vincent, M.; Marchand, B.; Rémond, G.; Jaguelin-Guinamant, S.; Damien, G.; Portevin, B.; Baumal, J. Y.; Volland, J. P.; Bouchet, J. P.; Lambert, P. H. Synthesis and ACE inhibitory activity of the stereoisomers of perindopril (S 9490) and perindoprilate (S 9780). Drug. Des. Discov. 1992, 9, 11-28.

127.

Thurieau, C.; Félétou, M.; Hennig, P.; Raimbaud, E.; Canet, E.; Fauchère, J.-L. Design and synthesis of new linear and cyclic bradykinin antagonists. J. Med. Chem. 1996, 39, 2095-2101.

128.

Caliendo, G.; Calignano, A.; Grieco, P.; Mancuso, F.; Perisutti, E.; Santini, A.; Santagada, V. Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids. Biopolymers 1995, 36, 409-414.

129.

Hashimoto, K.; Saito, B.; Miyamoto, N.; Oguro, Y.; Tomita, D.; Shiokawa, Z.; Asano, M.; Kakei, H.; Taya, N.; Kawasaki, M.; Sumi, H.; Yabuki, M.; Iwai, K.; Yoshida, S.; Yoshimatsu, M.; Aoyama, K.; Kosugi, Y.; Kojima, T.; Morishita, N.; Dougan, D. R.; Snell, G. P.; Imamura, S.; Ishikawa, T. Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic. J. Med.Chem. 2013, 56, 1228-1246.

130.

Condon, S. M.; Mitsuuchi, Y.; Deng, Y.; LaPorte, M. G.; Rippin, S. R.; Haimowitz, T.; Alexander, M. D.; Kumar, P. T.; Hendi, M. S.; Lee, Y. H.; Benetatos, C. A.; Yu, G.; Kapoor, G. S.; Neiman, E.; Seipel, M. E.; Burns, J. M.; Graham, M. A.; McKinlay, M. A.; Li, X.; Wang, J.; Shi, Y.; Feltham, R.; Bettjeman, B.; Cumming, M. H.; Vince, J. E.; Khan, N.; Silke, J.; Day, C. L.; Chunduru, S. K. Birinapant, a SMAC-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. J. Med.Chem. 2014, 57, 3666-3677.


Page 83 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

131.


Saro, D.; Klosi, E.; Paredes, A.; Spaller, M. R. Thermodynamic analysis of a hydrophobic binding site: Probing the PDZ domain with nonproteinogenic peptide ligands. Org. Lett. 2004, 6, 3429-3432.

132.

Hardes, K.; Becker, G. L.; Lu, Y.; Dahms, S. O.; Kohler, S.; Beyer, W.; Sandvig, K.; Yamamoto, H.; Lindberg, I.; Walz, L.; von Messling, V.; Than, M. E.; Garten, W.; Steinmetzer, T. Novel furin inhibitors with potent anti-infectious activity. ChemMedChem 2015, 10, 12181231.

133.

Khosla, M. C.; Leese, R. A.; Maloy, W. L.; Ferreira, A. T.; Smeby, R. R.; Bumpus, F. M. Synthesis of some analogs of angiotensin ii as specific antagonists of the parent hormone. J. Med.Chem. 1972, 15, 792-795.

134.

Fletcher, G. A.; Young, G. T. Amino-acids and peptides. Part xxxvi. The synthesis of analogues of bradykinin by the picolyl ester method. J. Chem. Soc., Perkin Trans. 1 1972, 1867-1874.

135.

Jorgensen, E. C.; Rapaka, S. R.; Windridge, G. C. Angiotensin ii analogs. 6. Stereochemical factors in the 5 position influencing pressor activity. 1. J. Med.Chem. 1971, 14, 899-903.

136.

Eisler, K.; Rudinger, J.; Šorm, F. Amino acids and peptides. Lxv. Analogues of oxytocin with isoleucine replaced by L-diethylalanine, L-cyclopentylglycine, and L- and D-cyclohexylglycine. Collect. Czech. Chem. Commun. 1966, 31, 4563-4580.

137.

Schwyzer, R.; Do, K. Q.; Eberle, A. N.; Fauchére, J.-L. Synthesis and biological properties of enkephalin-like peptides containing carboranylalanine in place of phenylalanine. Helv. Chim. Acta 1981, 64, 2078-2083.

138.

Larsson, U.; Carlson, R.; Leroy, J. Synthesis of amino acids with modified principal properties. 1. Amino acids with fluorinated side chains. Acta Chem. Scand. 1993, 47, 380-390.

139.

Vine, W. H.; Hsieh, K.-H.; Marshall, G. R. Synthesis of fluorine-containing peptides. Analogs of angiotensin II containing hexafluorovaline. J. Med. Chem. 1981, 24, 1043-1047.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

140.

Page 84 of 96

Tacke, R.; Merget, M.; Bertermann, R.; Bernd, M.; Beckers, T.; Reissmann, T. Syntheses and properties of silicon- and germanium-containing α-amino acids and peptides: A study on C/Si/Ge bioisosterism. Organometallics 2000, 19, 3486-3497.

141.

Cavelier, F.; Vivet, B.; Martinez, J.; Aubry, A.; Didierjean, C.; Vicherat, A.; Marraud, M. Influence of silaproline on peptide conformation and bioactivity. J. Am. Chem. Soc. 2002, 124, 2917-2923.

142.

Geistlinger, T. R.; Guy, R. K. Novel selective inhibitors of the interaction of individual nuclear hormone receptors with a mutually shared steroid receptor coactivator 2. J. Am. Chem. Soc. 2003, 125, 6852-6853.

143.

Yao, N.; Xiao, W.; Meza, L.; Tseng, H.; Chuck, M.; Lam, K. S. Structure-activity relationship studies of targeting ligands against breast cancer cells. J. Med.Chem. 2009, 52, 6744-6751.

144.

Guerrini, R.; Caló, G.; Bigoni, R.; Rizzi, D.; Rizzi, A.; Zucchini, M.; Varani, K.; Hashiba, E.; Lambert, D. G.; Toth, G.; Borea, P. A.; Salvadori, S.; Regoli, D. Structure−activity studies of the Phe4 residue of nociceptin(1−13)-NH2: Identification of highly potent agonists of the nociceptin/orphanin FQ receptor. J. Med. Chem. 2001, 44, 3956-3964.

145.

Mierke, D. F.; Said-Nejad, O. E.; Schiller, P. W.; Goodman, M. Enkephalin analogues containing beta-naphthylalanine at the fourth position. Biopolymers 1990, 29, 179-196.

146.

Lammek, B.; Czaja, M.; Derdowska, I.; Rekowski, P.; Trzeciak, H. I.; Sikora, P.; Szkrobka, W.; Stojko, R.; Kupryszewski, G. Influence of L-naphthylalanine in position 3 of AVP and its analogues on their pharmacological properties. J. Pept. Res. 1997, 49, 261-268.

147.

Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.; Li, X.; Grobelny, D.; Casabonne, M.; Tyrrell, D.; Holme, K.; Nadzan, A.; Galardy, R. E. Matrix metalloproteinase inhibitors: A structure-activity study. J. Med.Chem. 1998, 41, 199-223.


Page 85 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

148.


Nestor, J. J.; Ho, T. L.; Simpson, R. A.; Horner, B. L.; Jones, G. H.; McRae, G. I.; Vickery, B. H. Synthesis and biological activity of some very hydrophobic superagonist analogs of luteinizing hormone-releasing hormone. J. Med. Chem. 1982, 25, 795-801.

149.

Hagiwara, D.; Miyake, H.; Igari, N.; Karino, M.; Maeda, Y.; Fujii, T.; Matsuo, M. Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance p antagonists: N2-[(4r)-4-hydroxy-1-[(1-methyl-1h-indol-3-yl)carbonyl]-l-prolyl]-Nmethyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and its related compounds. J. Med. Chem. 1994, 37, 2090-2099.

150.

Josien, H.; Lavielle, S.; Brunissen, A.; Saffroy, M.; Torrens, Y.; Beaujouan, J.-C.; Glowinski, J.; Chassaing, G. Design and synthesis of side-chain conformationally restricted phenylalanines and their use for structure-activity studies on tachykinin NK-1 receptor. J. Med. Chem. 1994, 37, 1586-1601.

151.

E. Gibson, S.; Guillo, N.; J. Middleton, R.; Thuilliez, A.; J. Tozer, M. Synthesis of conformationally constrained phenylalanine analogues via 7-, 8- and 9-endo heck cyclisations. J. Chem. Soc., Perkin Trans. 1 1997, 447-456.

152.

Hruby, V. J. Conformational and topographical considerations in the design of biologically active peptides. Biopolymers 1993, 33, 1073-1082.

153.

Kövér, K. E.; Jiao, D.; Fang, S.; Hruby, V. J. Conformational analysis of four βmethylphenylalanine stereoisomers in a bioactive peptide by z-filtered relay NMR spectroscopy. Magnet. Res. Chem. 1993, 31, 1072-1076.

154.

Haskell-Luevano, C.; Toth, K.; Boteju, L.; Job, C.; Castrucci, A. M.; Hadley, M. E.; Hruby, V. J. Beta-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligandreceptor interactions and prolonged biological activity. J. Med.Chem. 1997, 40, 2740-2749.

155.

Tourwe, D.; Mannekens, E.; Diem, T. N.; Verheyden, P.; Jaspers, H.; Toth, G.; Peter, A.; Kertesz, I.; Torok, G.; Chung, N. N.; Schiller, P. W. Side chain methyl substitution in the delta85 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 86 of 96

opioid receptor antagonist tipp has an important effect on the activity profile. J. Med.Chem. 1998, 41, 5167-5176. 156.

Solanas, C.; de la Torre, B. G.; Fernandez-Reyes, M.; Santiveri, C. M.; Jimenez, M. A.; Rivas, L.; Jimenez, A. I.; Andreu, D.; Cativiela, C. Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin s. J. Med.Chem. 2010, 53, 4119-4129.

157.

Blaskovich, M. A. Drug discovery and protein tyrosine phosphatases. Curr .Med. Chem. 2009, 16, 2095-2176.

158.

Hirayama, R.; Yamamoto, M.; Tsukida, T.; Matsuo, K.; Obata, Y.; Sakamoto, F.; Ikeda, S. Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Biorg. Med. Chem. 1997, 5, 765-778.

159.

Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.; Li, X.; Grobelny, D.; Casabonne, M.; Tyrrell, D.; Holme, K.; Nadzan, A.; Galardy, R. E. Matrix metalloproteinase inhibitors: A structure−activity study. J. Med. Chem. 1998, 41, 199-223.

160.

Gibson, S. E.; Guillo, N.; Tozer, M. J. Towards control of χ-space: Conformationally constrained analogues of Phe, Tyr, Trp and His. Tetrahedron 1999, 55, 585-615.

161.

Rosenberg, S. H.; Spina, K. P.; Woods, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L. Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides. J. Med. Chem. 1993, 36, 449-459.

162.

Sievertsson, H.; Chang, J.-K.; Folkers, K.; Bowers, C. Y. Hypothalamic hormones. 32. Role of the histadine moiety in the structure of the thyrotropin-releasing hormone. J. Med. Chem. 1972, 15, 219-221.

163.

Bladon, C. M. Synthesis of heteroaromatic thyrotropin-releasing hormone analogues. J. Chem. Soc., Perkin Trans. 1 1990, 1151-1158.

164.

Hsieh, K.-H.; Jorgensen, E. C.; Lee, T. C. Angiotensin II analogs. 14. Roles of the imidazole nitrogens of position-6 histidine in pressor activity. J. Med. Chem. 1979, 22, 1199-1206. 86 ACS Paragon Plus Environment

Page 87 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

165.


Singam, P. R.; Bradshaw, C. W.; Menzia, J. A.; Narayanan, B. A.; Rockway, T. W.; Welch, N.; Tien, J.-H. J. An efficient process for the synthesis of renin inhibitor, ABT-517. Synth. Commun. 1996, 26, 2751-2756.

166.

Schiefer, I. T.; Tapadar, S.; Litosh, V.; Siklos, M.; Scism, R.; Wijewickrama, G. T.; Chandrasena, E. P.; Sinha, V.; Tavassoli, E.; Brunsteiner, M.; Fa, M.; Arancio, O.; Petukhov, P.; Thatcher, G. R. Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors. J. Med.Chem. 2013, 56, 6054-6068.

167.

Hapău, D.; Rémond, E.; Fanelli, R.; Vivancos, M.; René, A.; Côté, J.; Besserer-Offroy, É.; Longpré, J.-M.; Martinez, J.; Zaharia, V.; Sarret, P.; Cavelier, F. Stereoselective synthesis of β(5-arylthiazolyl) α-amino acids and use in neurotensin analogues. Eur. J. Org. Chem. 2016, 2016, 1017-1024.

168.

Rosowsky, A.; Forsch, R.; Uren, J.; Wick, M.; Kumar, A. A.; Freisheim, J. H. Methotrexate analogs. 20. Replacement of glutamate by longer-chain amino diacids: Effects on dihydrofolate reductase inhibition, cytotoxicity, and in vivo antitumor activity. J. Med. Chem. 1983, 26, 17191724.

169.

Li, P.; Zhang, M.; Long, Y.-Q.; Peach, M. L.; Liu, H.; Yang, D.; Nicklaus, M.; Roller, P. P. Potent GRB2–SH2 domain antagonists not relying on phosphotyrosine mimics. Bioorg. Med. Chem. Lett. 2003, 13, 2173-2177.

170.

St Laurent, D. R.; Balasubramanian, N.; Han, W. T.; Trehan, A.; Federici, M. E.; Meanwell, N. A.; Wright, J. J.; Seiler, S. M. Active site-directed thrombin inhibitors-II. Studies related to arginine/guanidine bioisosteres. Biorg. Med. Chem. 1995, 3, 1145-1156.

171.

Sturzebecher, J.; Prasa, D.; Hauptmann, J.; Vieweg, H.; Wikstrom, P. Synthesis and structureactivity relationships of potent thrombin inhibitors: Piperazides of 3-amidinophenylalanine. J. Med.Chem. 1997, 40, 3091-3099.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

172.

Page 88 of 96

Oh, Y. S.; Yun, M.; Hwang, S. Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K. H.; Yoo, Y. J.; Kim, D. S.; Lee, S. H.; Lee, Y. H.; Park, H. D.; Lee, C. H.; Lee, S. K.; Kim, S. Discovery of LB30057, a benzamidrazone-based selective oral thrombin inhibitor. Bioorg. Med. Chem. Lett. 1998, 8, 631634.

173.

Rewinkel, J. B. M.; Lucas, H.; van Galen, P. J. M.; Noach, A. B. J.; van Dinther, T. G.; Rood, A. M. M.; Jenneboer, A. J. S. M.; van Boeckel, C. A. A. 1-aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 685-690.

174.

Weigel, L. F.; Nitsche, C.; Graf, D.; Bartenschlager, R.; Klein, C. D. Phenylalanine and phenylglycine analogues as arginine mimetics in dengue protease inhibitors. J. Med. Chem. 2015, 58, 7719-7733.

175.

Van Nispen, J. W.; Tesser, G. I.; Nivard, R. J. F. Synthesis and biological activities of two ACTH-analgues containing L-norarginine in position 8. Int. J. Pept. Protein Res. 1977, 9, 193202.

176.

Moore, S.; Law, H. D.; Brundish, D. E.; Elliott, D. F.; Wade, R. Synthesis of analogues of bradykinin with replacement of the arginine residues by 4-guanidinophenyl-L-alanine. J. Chem. Soc., Perkin Trans. 1 1977, 2025-2030.

177.

Xu, P.; Xu, M.; Jiang, L.; Yang, Q.; Luo, Z.; Dauter, Z.; Huang, M.; Andreasen, P. A. Design of specific serine protease inhibitors based on a versatile peptide scaffold: Conversion of a urokinase inhibitor to a plasma kallikrein inhibitor. J. Med. Chem. 2015, 58, 8868-8876.

178.

Gazdik, M.; Jarman, K. E.; O’Neill, M. T.; Hodder, A. N.; Lowes, K. N.; Jousset Sabroux, H.; Cowman, A. F.; Boddey, J. A.; Sleebs, B. E. Exploration of the p3 region of pexel peptidomimetics leads to a potent inhibitor of the plasmodium protease, plasmepsin V. Biorg. Med. Chem. 2016, 24, 1993-2010.


Page 89 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

179.


Ravikumar, Y.; Nadarajan, S. P.; Yoo, T. H.; Lee, C. S.; Yun, H. Unnatural amino acid mutagenesis-based enzyme engineering. Trends Biotechnol. 2015, 33, 462-470.

180.

Gong, Y.; Pan, L. Recent advances in bioorthogonal reactions for site-specific protein labeling and engineering. Tetrahedron Lett. 2015, 56, 2123-2132.

181.

Krall, N.; da Cruz, F. P.; Boutureira, O.; Bernardes, G. J. L. Site-selective protein-modification chemistry for basic biology and drug development. Nat. Chem. 2016, 8, 103-113.

182.

Chin, J. W.; Cropp, T. A.; Anderson, J. C.; Mukherji, M.; Zhang, Z.; Schultz, P. G. An expanded eukaryotic genetic code. Science 2003, 301, 964-967.

183.

Wang, L.; Zhang, Z.; Brock, A.; Schultz, P. G. Addition of the keto functional group to the genetic code of escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 56-61.

184.

Link, A. J.; Vink, M. K. S.; Tirrell, D. A. Presentation and detection of azide functionality in bacterial cell surface proteins. J. Am. Chem. Soc. 2004, 126, 10598-10602.

185.

Amiram, M.; Haimovich, A. D.; Fan, C.; Wang, Y.-S.; Aerni, H.-R.; Ntai, I.; Moonan, D. W.; Ma, N. J.; Rovner, A. J.; Hong, S. H.; Kelleher, N. L.; Goodman, A. L.; Jewett, M. C.; Soll, D.; Rinehart, J.; Isaacs, F. J. Evolution of translation machinery in recoded bacteria enables multisite incorporation of nonstandard amino acids. Nat. Biotech. 2015, 33, 1272-1279.

186.

Barrett, J. E.; Lucero, C. M.; Schultz, P. G. A model for hydride transfer in thymidylate synthase based on unnatural amino acid mutagenesis. J. Am. Chem. Soc. 1999, 121, 7965-7966.

187.

Cho, H.; Daniel, T.; Buechler, Y. J.; Litzinger, D. C.; Maio, Z.; Putnam, A.-M. H.; Kraynov, V. S.; Sim, B.-C.; Bussell, S.; Javahishvili, T.; Kaphle, S.; Viramontes, G.; Ong, M.; Chu, S.; GC, B.; Lieu, R.; Knudsen, N.; Castiglioni, P.; Norman, T. C.; Axelrod, D. W.; Hoffman, A. R.; Schultz, P. G.; DiMarchi, R. D.; Kimmel, B. E. Optimized clinical performance of growth hormone with an expanded genetic code. Proc. Natl. Acad. Sci. 2011, 108, 9060-9065.

188.

Tian, F.; Lu, Y.; Manibusan, A.; Sellers, A.; Tran, H.; Sun, Y.; Phuong, T.; Barnett, R.; Hehli, B.; Song, F.; DeGuzman, M. J.; Ensari, S.; Pinkstaff, J. K.; Sullivan, L. M.; Biroc, S. L.; Cho, 89 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 90 of 96

H.; Schultz, P. G.; DiJoseph, J.; Dougher, M.; Ma, D.; Dushin, R.; Leal, M.; Tchistiakova, L.; Feyfant, E.; Gerber, H.-P.; Sapra, P. A general approach to site-specific antibody drug conjugates. Proc. Natl. Acad. Sci. 2014, 111, 1766-1771. 189.

Zimmerman, E. S.; Heibeck, T. H.; Gill, A.; Li, X.; Murray, C. J.; Madlansacay, M. R.; Tran, C.; Uter, N. T.; Yin, G.; Rivers, P. J.; Yam, A. Y.; Wang, W. D.; Steiner, A. R.; Bajad, S. U.; Penta, K.; Yang, W.; Hallam, T. J.; Thanos, C. D.; Sato, A. K. Production of site-specific antibody– drug conjugates using optimized non-natural amino acids in a cell-free expression system. Bioconj. Chem. 2014, 25, 351-361.

190.

Halford, B. First-time disclosure of clinical candidates at #acssandiego. http://acssandiego2016.cenmag.org/first-time-disclosure-of-clinical-candidates-at-acssandiego/ (accessed June 2 2016).

191.

Dosio, F.; Brusa, P.; Cattel, L. Immunotoxins and anticancer drug conjugate assemblies: The role of the linkage between components. Toxins (Basel) 2011, 3, 848.

192.

Wojcik, P.; Berlicki, L. Peptide-based inhibitors of protein-protein interactions. Bioorg. Med. Chem. Lett. 2016, 26, 707-713.

193.

Werner, H. M.; Cabalteja, C. C.; Horne, W. S. Peptide backbone composition and protease susceptibility: Impact of modification type, position, and tandem substitution. ChemBioChem 2016, 17, 712-718.

194.

Cai, M.; Marelli, U. K.; Bao, J.; Beck, J. G.; Opperer, F.; Rechenmacher, F.; McLeod, K. R.; Zingsheim, M. R.; Doedens, L.; Kessler, H.; Hruby, V. J. Systematic backbone conformational constraints on a cyclic melanotropin ligand leads to highly selective ligands for multiple melanocortin receptors. J. Med.Chem. 2015, 58, 6359-6367.

195.

Nakajima, K.; April, M.; Brewer, J. T.; Daniels, T.; Forster, C. J.; Gilmore, T. A.; Jain, M.; Kanter, A.; Kwak, Y.; Li, J.; McQuire, L.; Serrano-Wu, M. H.; Streeper, R.; Szklennik, P.;


Page 91 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Thompson, J.; Wang, B. Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 1245-1248. 196.

Rotella, D. P. The discovery and development of boceprevir. Expert Opin. Drug. Discov. 2013, 8, 1439-1447.

197.

Kwong, A. D.; Kauffman, R. S.; Hurter, P.; Mueller, P. Discovery and development of telaprevir: An NS3-4a protease inhibitor for treating genotype 1 chronic hepatitis c virus. Nat. Biotech. 2011, 29, 993-1003.

198.

Llinàs-Brunet, M.; Bailey, M. D.; Goudreau, N.; Bhardwaj, P. K.; Bordeleau, J.; Bös, M.; Bousquet, Y.; Cordingley, M. G.; Duan, J.; Forgione, P.; Garneau, M.; Ghiro, E.; Gorys, V.; Goulet, S.; Halmos, T.; Kawai, S. H.; Naud, J.; Poupart, M.-A.; White, P. W. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis c virus NS3 protease (BI 201335). J. Med. Chem. 2010, 53, 6466-6476.

199.

Scola, P. M.; Sun, L.-Q.; Wang, A. X.; Chen, J.; Sin, N.; Venables, B. L.; Sit, S.-Y.; Chen, Y.; Cocuzza, A.; Bilder, D. M.; D’Andrea, S. V.; Zheng, B.; Hewawasam, P.; Tu, Y.; Friborg, J.; Falk, P.; Hernandez, D.; Levine, S.; Chen, C.; Yu, F.; Sheaffer, A. K.; Zhai, G.; Barry, D.; Knipe, J. O.; Han, Y.-H.; Schartman, R.; Donoso, M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Good, A. C.; Rajamani, R.; Kish, K.; Tredup, J.; Klei, H. E.; Gao, Q.; Mueller, L.; Colonno, R. J.; Grasela, D. M.; Adams, S. P.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.; Warner, W.; Li, D.; Zhu, J.; Meanwell, N. A.; McPhee, F. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis c virus infection. J. Med. Chem. 2014, 57, 1730-1752.

200.

Scola, P. M.; Wang, A. X.; Good, A. C.; Sun, L. Q.; Combrink, K. D.; Campbell, J. A.; Chen, J.; Tu, Y.; Sin, N.; Venables, B. L.; Sit, S. Y.; Chen, Y.; Cocuzza, A.; Bilder, D. M.; D'Andrea, S.; Zheng, B.; Hewawasam, P.; Ding, M.; Thuring, J.; Li, J.; Hernandez, D.; Yu, F.; Falk, P.; Zhai, G.; Sheaffer, A. K.; Chen, C.; Lee, M. S.; Barry, D.; Knipe, J. O.; Li, W.; Han, Y. H.; Jenkins, 91 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 92 of 96

S.; Gesenberg, C.; Gao, Q.; Sinz, M. W.; Santone, K. S.; Zvyaga, T.; Rajamani, R.; Klei, H. E.; Colonno, R. J.; Grasela, D. M.; Hughes, E.; Chien, C.; Adams, S.; Levesque, P. C.; Li, D.; Zhu, J.; Meanwell, N. A.; McPhee, F. Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis c virus infection. J. Med.Chem. 2014, 57, 1708-1729. 201.

LaPlante, S. R.; Nar, H.; Lemke, C. T.; Jakalian, A.; Aubry, N.; Kawai, S. H. Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis c virus NS3 protease. J. Med.Chem. 2014, 57, 1777-1789.

202.

Sato, T.; Izawa, K.; Aceña, J. L.; Liu, H.; Soloshonok, V. A. Tailor-made α-amino acids in the pharmaceutical industry: Synthetic approaches to (1R,2S)-1-amino-2-vinylcyclopropane-1carboxylic acid (vinyl-ACCA). Eur. J. Org. Chem. 2016, 2016, 2757-2774.

203.

Jiang, Y.; Andrews, S. W.; Condroski, K. R.; Buckman, B.; Serebryany, V.; Wenglowsky, S.; Kennedy, A. L.; Madduru, M. R.; Wang, B.; Lyon, M.; Doherty, G. A.; Woodard, B. T.; Lemieux, C.; Do, M. G.; Zhang, H.; Ballard, J.; Vigers, G.; Brandhuber, B. J.; Stengel, P.; Josey, J. A.; Beigelman, L.; Blatt, L.; Seiwert, S. D. Discovery of danoprevir (ITMN-191/r7227), a highly selective and potent inhibitor of hepatitis c virus (HCV) NS3/4a protease. J. Med. Chem. 2014, 57, 1753-1769.

204.

Llinàs-Brunet, M.; Bailey, M. D.; Bolger, G.; Brochu, C.; Faucher, A.-M.; Ferland, J. M.; Garneau, M.; Ghiro, E.; Gorys, V.; Grand-Maître, C.; Halmos, T.; Lapeyre-Paquette, N.; Liard, F.; Poirier, M.; Rhéaume, M.; Tsantrizos, Y. S.; Lamarre, D. Structure−activity study on a novel series of macrocyclic inhibitors of the hepatitis c virus NS3 protease leading to the discovery of BILN 2061. J. Med. Chem. 2004, 47, 1605-1608.

205.

Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; 92 ACS Paragon Plus Environment

Page 93 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


St George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llinas-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis c virus. Nature 2003, 426, 186-189. 206.

Moreau, B.; O'Meara, J. A.; Bordeleau, J.; Garneau, M.; Godbout, C.; Gorys, V.; Leblanc, M.; Villemure, E.; White, P. W.; Llinas-Brunet, M. Discovery of hepatitis c virus NS3-4a protease inhibitors with improved barrier to resistance and favorable liver distribution. J. Med.Chem. 2014, 57, 1770-1776.

207.

Rosenquist, Å.; Samuelsson, B.; Johansson, P.-O.; Cummings, M. D.; Lenz, O.; Raboisson, P.; Simmen, K.; Vendeville, S.; de Kock, H.; Nilsson, M.; Horvath, A.; Kalmeijer, R.; de la Rosa, G.; Beumont-Mauviel, M. Discovery and development of simeprevir (TMC435), a HCV NS3/4a protease inhibitor. J. Med. Chem. 2014, 57, 1673-1693.

208.

Alexandre, F. R.; Brandt, G.; Caillet, C.; Chaves, D.; Convard, T.; Derock, M.; Gloux, D.; Griffon, Y.; Lallos, L.; Leroy, F.; Liuzzi, M.; Loi, A. G.; Moulat, L.; Musiu, C.; Parsy, C.; Rahali, H.; Roques, V.; Seifer, M.; Standring, D.; Surleraux, D. Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis c virus NS3/4a serine protease. Bioorg. Med. Chem. Lett. 2015, 25, 3984-3991.

209.

Parsy, C. C.; Alexandre, F.-R.; Bidau, V.; Bonnaterre, F.; Brandt, G.; Caillet, C.; Cappelle, S.; Chaves, D.; Convard, T.; Derock, M.; Gloux, D.; Griffon, Y.; Lallos, L. B.; Leroy, F.; Liuzzi, M.; Loi, A.-G.; Moulat, L.; Chiara, M.; Rahali, H.; Roques, V.; Rosinovsky, E.; Savin, S.; Seifer, M.; Standring, D.; Surleraux, D. Discovery and structural diversity of the hepatitis c virus NS3/4a serine protease inhibitor series leading to clinical candidate IDX320. Bioorg. Med. Chem. Lett. 2015, 25, 5427-5436.

210.

McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.; Nguyen, K. T.; Romano, J. J.; Butcher, J. W.; Gilbert, K. F.; Bush, K. J.; Holloway, M. K.; Swestock, J.; Wan, B.-L.; Carroll, S. S.; DiMuzio, J. M.; Graham, D. J.; Ludmerer, S. W.; Mao, S.-S.; Stahlhut, M. W.; Fandozzi, C. M.; Trainor, 93 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 94 of 96

N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis c virus NS3/4a protease inhibitor. J. Med. Chem. 2010, 53, 2443-2463. 211.

Harper, S.; McCauley, J. A.; Rudd, M. T.; Ferrara, M.; DiFilippo, M.; Crescenzi, B.; Koch, U.; Petrocchi, A.; Holloway, M. K.; Butcher, J. W.; Romano, J. J.; Bush, K. J.; Gilbert, K. F.; McIntyre, C. J.; Nguyen, K. T.; Nizi, E.; Carroll, S. S.; Ludmerer, S. W.; Burlein, C.; DiMuzio, J. M.; Graham, D. J.; McHale, C. M.; Stahlhut, M. W.; Olsen, D. B.; Monteagudo, E.; Cianetti, S.; Giuliano, C.; Pucci, V.; Trainor, N.; Fandozzi, C. M.; Rowley, M.; Coleman, P. J.; Vacca, J. P.; Summa, V.; Liverton, N. J. Discovery of MK-5172, a macrocyclic hepatitis c virus NS3/4a protease inhibitor. ACS Med. Chem. Lett. 2012, 3, 332-336.

212.

Raja, A.; Lebbos, J.; Kirkpatrick, P. Atazanavir sulphate. Nat. Rev. Drug Discov. 2003, 2, 857858.

213.

Xu, L.; Liu, H.; Murray, B. P.; Callebaut, C.; Lee, M. S.; Hong, A.; Strickley, R. G.; Tsai, L. K.; Stray, K. M.; Wang, Y.; Rhodes, G. R.; Desai, M. C. Cobicistat (GS-9350): A potent and selective inhibitor of human CYP3a as a novel pharmacoenhancer. ACS Med. Chem. Lett. 2010, 1, 209-213.

214.

Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J. D.; Chen, I.-W.; WVastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 40964100.

215.

Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; W., L. R.; H., M. J.; S., M. J.; B., P. K. E.; S., R.; J., R. A.; L., T. D.; J., T. G.; J., M. P. Rational design of peptide-based HIV proteinase inhibitors. Science 1990, 248, 358-361. 94 ACS Paragon Plus Environment

Page 95 of 96

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

216.


Mosberg, H. I.; Yeomans, L.; Anand, J. P.; Porter, V.; Sobczyk-Kojiro, K.; Traynor, J. R.; Jutkiewicz, E. M. Development of a bioavailable mu opioid receptor (mopr) agonist, delta opioid receptor (dopr) antagonist peptide that evokes antinociception without development of acute tolerance. J. Med.Chem. 2014, 57, 3148-3153.

217.

Huffman, M. A.; Reider, P. J. Improved stereoselectivity in the heterogeneous catalytic synthesis of enalapril obtained through multidimensional screening. Tetrahedron Lett. 1999, 40, 831-834.

218.

Natesh, R.; Schwager, S. L. U.; Sturrock, E. D.; Acharya, K. R. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 2003, 421, 551-554.

219.

Kim, K. B.; Crews, C. M. From epoxomicin to carfilzomib: Chemistry, biology, and medical outcomes. Nat. Prod. Rep. 2013, 30, 600-604.

220.

Liu, Q. Y.; Yang, Q.; Sun, W. M.; Vogel, P.; Heydorn, W.; Yu, X. Q.; Hu, Z. X.; Yu, W. S.; Jonas, B.; Pineda, R.; Calderon-Gay, V.; Germann, M.; O'Neill, E.; Brommage, R.; Cullinan, E.; Platt, K.; Wilson, A.; Powell, D.; Sands, A.; Zambrowicz, B.; Shi, Z. C. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J. Pharmacol. Exp. Ther. 2008, 325, 47-55.

221.

Goldberg, D. R.; De Lombaert, S.; Aiello, R.; Bourassa, P.; Barucci, N.; Zhang, Q.; Paralkar, V.; Valentine, J.; Zavadoski, W. Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 1124-1129.

222.

Morel, A. F.; Flach, A.; Zanatta, N.; Ethur, E. M.; Mostardeiro, M. A.; Gehrke, I. T. S. A new cyclopeptide alkaloid from the bark of waltheria douradinha. Tetrahedron Lett. 1999, 40, 92059209.



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