Unusual Amino Acids in Medicinal Chemistry - Journal of Medicinal

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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 functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially diverse side chains provides a unique three-dimensional structure with a 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-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

1. INTRODUCTION Amino acids have played a significant role in drugs from the earliest days of modern drug discovery; they are contained in natural products such as the antibiotics bacitracin and vancomycin and in peptides such as insulin. They are indispensable components of 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 derivatizable) 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 (1)4 and pyrrolysine (2)5 (Scheme 1). The “proteinogenic” classification is also misleading, as noncoded 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 post-translational modifications (acylation, phosphorylation, sulfation, glycosylation, hydroxylation, oxidation, nitration, methylation, and prenylation) of residues, and tertiary from post-translational cross-linking of two amino acids.6 In contrast, the nonprotein 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 nonprotein amino acids are formed as secondary © 2016 American Chemical Society

Scheme 1. Naturally Occurring Unusual Amino Acids

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. This perspective will describe a range of approved and clinical stage drugs that incorporate amino acids with unusual structures, and will 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, as they are often incorporated into peptides to reduce proteolysis), deuterated amino acids (incorporated to reduce metabolism or Received: March 2, 2016 Published: September 2, 2016 10807

DOI: 10.1021/acs.jmedchem.6b00319 J. Med. Chem. 2016, 59, 10807−10836

Journal of Medicinal Chemistry

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Scheme 2. β- and γ-Amino Acids in Drugs

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 dipeptides), 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 3−6). 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, 2-amino3-(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, 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 1-aminocycloalkyl-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 amnesic shellfish poisoning. Hundreds of analogs have been synthesized, with a number of highly constrained bicyclic derivatives reaching clinical trials. 14 (LY404039),

racemization), or radiolabeled amino acids (other than a few examples of those used clinically; many analogs are used for metabolite studies). The β-, γ-, and δ-amino acids (Scheme 2), while forming important components of drugs such as the anticancer agents paclitaxel (Taxol) (6) (containing phenylisoserine) and ubenimex/bestatin (7) (3-amino-2-hydroxy-4phenylbutanoic 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-2-yl)acetate), and anticonvulsant gabapentin (10) (1-(aminomethyl)cyclohexaneacetic acid), are generally beyond the scope of this perspective. Scheme 3. Free Excitatory Imino Acids

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Scheme 4. Aromatic and Heteroaromatic Free Amino Acid Drugs

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 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-5methylisoxazol-4-yl)acetic acid (AMMA) (24) is a specific agonist of NMDA receptors.21 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. α-Methylation 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 the 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-3,4dihydroxy-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-(2,6diiodo-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 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 tumors.30 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 4 g of L-Trp per day for 4 days, and 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 in a net loss of hair due to the normal loss of resting hair. This phenomenom was observed in animals and native women 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) as an intermediate.35 Overproduction of NO is implicated in a range of 10809



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Scheme 5. Other Bioactive Free Amino Acids

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 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 O-methyl−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, α-hydroxy-Gly, is found at the core of 15-deoxyspergualin (68) (gusperimus). This antitumor antibiotic isolated from the bacteria Bacillus laterosporus

has been studied in several clinical trials for the treatment of cancer.54 cis-4,5-Epoxy-L-pipecolic acid (53) is a mechanism-based inhibitor of L-pipecolate oxidase, a potential target for treating convulsive disorders, as it is involved in the degradation of Lys. trans-3,4-Epoxy-Pro (54) acts as a reversible inhibitor. D-Penicillamine (D-β,β-dimethylcysteine) (55) is produced by hydrolysis of benzylpenicillin.31 It is used clinically as a chelating agent to eliminate toxic metal ions, and for severe rheumatoid arthritis.31 Radiolabeled amino acids (Scheme 6) have found significant use in oncological PET studies. Tumor cells tend to have Scheme 6. Free Amino Acids Used for Imaging and Radiotherapy

a limited blood supply, and thus compensate by developing specialized transport systems to accumulate amino acids to meet their nutritional needs. Labeled amino acids can be employed to assess areas of increased amino acid uptake, with the difference used to distinguish between normal and pathological (tumorous) states; areas of tissue that accumulate more of the tracer will show as brighter or “hot spots” in the PET scan. [1-11C]-L-Met (56) is one of the most widely used amino acids for PET oncology, measuring the metabolic rate of protein synthesis in tissue.55 6′-18F-L-Dopa (57) is employed for PET studies to determine the regional distribution of the dopamine neurotransmitter in the brain,56 and O-[11C]methyl−L-Tyr (58) for PET studies of amino acid transport.57 Amino acids containing boron (Scheme 6) are of interest, primarily due to their potential use in boron neutron capture therapy (BNCT), a cancer therapy. The treatment is based on administration of a boron-containing compound that is selectively absorbed by tumorous cells. Irradiation of the target cells and surrounding tissue with thermal neutrons of subionizing energy causes the stable 10B isotope to absorb a neutron and emit a highly energetic α-particle and 7Li nucleus, which cause lethal radiation damage only within approximately one cell diameter.58 The most commonly used compound for BNCT has been L-p-boronophenylalanine (BPA) (59), which accumulates preferentially in melanoma cells.59 One method of increasing the effectiveness of BNCT is to increase the number of boron atoms within a molecule. BPA analogs 60 and 61 have been prepared, which contain polyhedral carboranes in the side chain, but the ortho- carboranylalanine did not selectively accumulate in mouse tumors.60 2.2. Amino Acids as Central Components of Drugs. A large number of drugs and biologically active molecules rely on a central unusual amino acid that is modified at either the N- or C-terminus, or both (Schemes 7−9). These can be 10811



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Scheme 7. Unusual Amino Acids as Central Components: α-Monosubstituted Amino Acids

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

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

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 10812



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

Decernotinib (82) (VX-509), a selective Janus tyrosine kinase 3 (JAK3) inhibitor for the treatment of autoimmune diseases, contains a central 2-amino-2-methylbutyric acid residue.76 The α-disubstitution can be combined with cyclization of the side chains to form cyclic amino acids: aminocyclobutane-1carbxylic 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-amino-4-carboxylic acid central residue.79 The same amino acid forms the core structure of opioid agonists carfentanil (86) and remifentanil (87), useful as anesthetics.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-methylPro 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 acetateinduced neutrophil migration and has completed a Phase 2 study for ulcerative colitis, the first FFA2 antagonist to reach the clinic.83 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 constraints and prevent exopeptidase proteolysis, with cyclizations generally achieved by head to tail lactam linkages, tail to

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 2,6-dimethylaniline; the S-enantiomer (72) was subsequently marketed as levobupivacaine.69 The cardioprotective nucleoside transport blocker draflazine (73) contains a piperazine-2-carboxylic acid amide with both imino nitrogens (two potential diversity points) N-alkylated.70 The antibiotic clindamycin (75) is a chemically modified (chlorinated) version of the natural product, lincomycin (74), 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 ethyl-substituted pipecolate 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 79 of the G-protein bile receptor, which showed efficacy at reducing peak glucose levels in genetically obese mice, and was derived from a piperidine-3carboxylic 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 80−81 that were effective inhibitors of integrin leukocyte function associated antigen 1 (LFA-1) in cell-based assays, with potential for cancer therapy.75 Conformational constraints are also introduced by using α,α-disubstituted amino acids (Scheme 9), which have the additional advantage of not being susceptible to racemization and of being less prone to proteolysis when included in peptides. 10813



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Scheme 10. Cyclic Peptide Hormones and Unusual Amino Acids in Cyclic Peptides

Scheme 11. Unusual Amino Acids in Cyclic Peptide Antibiotics

with dalfopristin as part of the antibiotic Synercid87) contains Phg, D-2-aminobutyric acid (D-Abu), N-methyl-4′-dimethyl-Phe, and an S-alkylated 4-oxo-5-thiomethylpipecolic 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

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 constraints, such as somatostatin 90, oxytocin 91, and closely related vasopressins 92 (Scheme 10). Cyclic peptide drugs range from those containing a single non-natural 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 O-benzyl Tyr, acylated hydroxyproline, and phenylglycine residues. 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 10814



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Scheme 12. Unusual Aromatic Amino Acids in Cyclic Peptide Antibiotics

Orn or 3,4-dihydroxy-Orn, 4-hydroxy-Pro, and 3-hydroxy-4methyl-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-3,4dihydroxy-Hfe in 107.93 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)-βhydroxy-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-hydroxyHis 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-(1-hydroxycyclopropyl)-Gly residue (cleonine) 110 replacing Thr.97 MeBmt (5), (4R)-[(E)-but-2-enyl]-4,N-dimethyl-L-threonine,

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. 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′-trihydroxyPhg 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 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 with dalbavancin possessing an additional biarylether-linked cyclic Phg ring system, similar to the natural product teicoplanin.91 A number of homologues of arylalanines are found in cyclic peptide antibiotics, such as 3-hydroxyhomotyrosine or 3,4dihydroxyhomotyrosine in the antifungal cyclic lipopeptides echinocandin B (103) and echinocandin D (104)92 along with 10815



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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 disulfidecontaining 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-cyclized peptides, leading to more stable analogues, such as in oxytocin analogues.99 Lanthionine (114) is a thioether analog of disulfidebridged cystine, with a one-atom shorter bridge. The nisin groups of polycyclic peptide antibiotics isolated from Streptococcus lactis contain both 114 and cystathionine 115 (the homologue of lanthionine which corresponds 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 Carbon-linked diaminodicarboxylic acids are useful as stable replacements for a cystine peptide bridge, with the application of diaminodicarboxylic acids for intermolecular peptide crosslinking 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 all-carbon 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, 2,5-diaminoadipic acid (119), and 2,9-diaminosebacic acid (120); the analog with 119 was 1000-fold more active than the original 118-based peptide.102 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

Scheme 13. Unusual Hydroxy Amino Acids in Naural Product Peptides

Scheme 14. Unusual Amino Acids Used for Peptide Cyclization

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Scheme 15. Diaminodicarboyxlic Acids for Cyclic Peptide Bridges

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

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 and 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 a β-hydroxy-Asp residue that forms an unstable 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 glycopeptide 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 acid)]naphthalene (126) to form one of the bridges.109 An imidazole-bridged diaminodicarboxylic 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 Alkene side chains of amino acids within peptides have been linked together by cross-metathesis to form cyclic systems. These “stapled peptides” are the key technology behind the biotech company Aileron Therapeutics, where they are used to bridge turns in helical peptides, stabilizing the secondary stucture. In early efforts, O-allyl-Ser (128) and O-allyl-homoserine (129) (Scheme 16) residues within a helical peptide were cross-linked by a Ru-catalyzed 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 10817



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

(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 cross-link residues in a favorable conformation, with the goal of stabilizing helix formation and improving peptide metabolic stability. Certain combinations of residues/ positions showed no cross-linking, while other couplings went to near completion, with a large 34-membered macrocycle forming rapidly and efficiently (12 carbons in the metathesized cross-link).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)-catalyzed azide−alkyne cycloaddition (CuAAC) “click” chemistry reaction between azides and alkynes.84 A number 10818



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Scheme 18. Sterically Hindered and Conformationally Constrained Amino Acids

reduces proteolysis, truncating the C-terminal Gly to an ethyl amide of the preceding Pro, and replacing the central Gly residue with an Nim-benzyl-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-D-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 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 contains D-2′-Nal, 4′-chloro-D-Phe, D-3′-pyridyl-Ala, and 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 Developed by Roche, it failed in Phase 3 trials due to side effects. α,αDiethylglycine has replaced Gly in an analog of a Pro-Leu-GlyNH2 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 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 tert-Leu (62) 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 1-amino-2-phenylcyclopropane-

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 cyclization. Screening identified XIAP inhibitors which were optimized 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), δ-azido-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 the i and i + 5 positions to maintain a common chain length and reproduce a type I β-turn.116 2.4. Unusual Amino Acids in Linear Peptides. Important linear peptide hormones include bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) (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, or luteinizing hormone-releasing hormone, LHRH: pyroGluHis-Trp-Ser-Tyr-Gly-Leu-Arg-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 (148),117 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-3-carboxylic 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 10819



Perspective

Scheme 19. Alkyl and Hydrophobic Amino Acids

Scheme 20. Aromatic Amino Acids

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 inhibitor with low pressor activity.125 10820



Perspective

Scheme 21. Aromatic Amino Acids: Phosphotyrosine Mimetics

Scheme 22. Trp and His Analogs

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 the inhibitor of apoptosis proteins (IAPs) that caused tumor regression in a MDA-MB-231 tumor xenograft model.129

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 antagonists,127 and antagonists of the NK-1 receptor,128 as was (S,S,S)-2-azabicyclo[3.3.0]octane-310821



Perspective

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. Amino Acids with Alkyl Side Chains. 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 second-generation 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 nonoxidizable Met replacement) (166), norleucine (Nle) (167), Val, Leu, Ile, and Tle (62)) were used to demonstrate that peptide binding affinities can be improved with a single nonstandard 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 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 Aromatic Amino Acids. The greatest diversity of amino acid side chains is found in substituted aromatic amino acids (arylglycine and arylalanines), which have 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′-difluoro-Phg, and 2′- or 3′-trifluoromethylPhg.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

Scheme 23. Acidic Amino Acids

of Phe4, with the Phe replacements including para-fluoro, -chloro, -bromo, -iodo, -nitro, -cyano, -trifluoromethyl, -methyl, -methoxy, -phenyl and -amino groups, meta- and ortho-fluoro, conformationally restricted α-, β-, or N-methyl-Phe, diphenylalanine 183, homophenylalanine 184, Phg 182, 1-naphthylalanine 185, and 2-naphthylalanine 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 were used to replace Phe in enkephalins,145 vasopressin antagonists,146 and orally active matrix metalloproteinase inhibitors.147 The D-enantiomers of 185 and 186, along with other hydrophobic Phe analogs, including 3′,4′,5′-trimethoxy-Phe, 2′,3′,4′,5′,6′-pentafluoro-Phe, β-(1-bromo-2-naphthyl)-Ala, 3′-trifluoromethyl-Phe, 4′-trifluoromethyl-Phe, 2′,4′,6′-trimethylPhe, 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 GnRH. The analogs containing β-(2-naphthyl)-DAla 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 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-dihydro-1,4-benzodioxin-6-yl)-Ala (189),149 or with a number of conformationally restricted 10822



Perspective

Scheme 24. Basic Amino Acids

Scheme 25. Unusual Amino Acids in Proteins

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),

Phe analogs (diphenylalanine (183), 1-indanylglycine (190), 2-indanylglycine (191), 9-fluorenylglycine (192), 1-benz[f]indanylglycine (193), (E)-dehydro-Phe (194), and (Z)-dehydroPhe (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 10823



Perspective

β-Me-Tyr (197b−200b), and β-Me-Tic have been systematically incorporated into the δ-opioid antagonist H-Tyr-Tic-Phe-PheOH, resulting in a profound influence on potency, selectivity, and signal transduction properties.155 A range of 12 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 nonhydrolyzable analogs of phosphoTyr (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 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. Heteroaromatic Amino Acids. 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 (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-1-yl)Ala (212), which were used for SAR studies directed toward the design of orally active renin inhibitors.161 The key His residue in the tripeptide thyrotropin releasing hormone (TRH, pyroGlu-HisPro-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)-LAla (213), β-(2-furyl)-L-Ala (214), and β-(2-pyrrolyl)-L- and 163 D-Ala (215) gave better results. The His-6 residue in angiotensin II was replaced with Dab (122), 4′-nitro-Phe, 4′-amino-Phe, β-(2-pyridyl)-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-(thiazol4-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 β-Arylthiazole alanines were recently incorporated into analogs of neurotensin (144), replacing Tyr11 and improving plasma stability and selectivity toward NTS1.167 Acidic Side Chains. Homologues 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 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 thrombin, Factor VIIa, and Factor Xa. However, the presence of the charged guanidine group generally precludes oral availability

Scheme 26. Peptide to Peptidomimetic Conversion

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 (231)176 and homoarginine (232)134 in bradykinin analogs. L-3-(N-Amidino-4piperidyl)-Ala (233) was incorporated into kallikrein inhibitors using a 10-mer cyclic peptide scaffold.177 A 2016 study tested 18 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 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 10824



Perspective

Scheme 27. Unusual Amino Acids in HCV Protease Inhibitor Peptidomimetics

acids, with 14 different Phe derivatives used as examples.185 A series of Trp analogs (5′-methyl-Trp, 4′,-, 5′-, or 6′-fluoroTrp, 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 Site-selective modifications will become increasingly 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, 236 was used as the attachment point to PEGylate human growth hormone at specific locations, improving its pharmacokinetic properties in clinical studies,187 and it 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 fragment.188 p-Azidomethyl-L-Phe (239) has also been used to ligate auristatin to an antibody,

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 and 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 Cu-catalyzed triazole formation with an alkyne linked to biotin and 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 multisite incorporation of unusual amino 10825



Perspective

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

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 C-terminal modified (242), then N-terminal modified (243), and then further derivatized to produce 245, with IC50 = 0.062 μM, improved solubility, gut permeability and metabolic stability, high oral bioavailability (76%), and oral efficacy.195 Attempts to remove the central amino acid residue produced an inactive compound 244. 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 and 28). Boceprevir 246 (SCH 503034) is a tripeptide with an N-terminal Boc-tert-Leu (Tle), a central bicyclic proline derivative, and a C-teminal cyclobutylalanine α-ketoamide analogue.196 Telaprevir (247) (Incivek, VX-950) is a similar tetrapeptide, but with an N-terminal pyrazine acyl group, followed by Chg, a different bicyclic Pro, and then a norvalinederived α-keto cyclopropylamide.197 In contrast, faldaprevir (248) (BI 201335)198 (abandoned after reaching Phase III) and asunaaprevir (249) (BMS650032)199 (still in Phase III trials) both retain an N-terminal Tle, but use a C-terminal 1-amino-2-vinylcyclopropyl-1carboxylic acid residue and a hydroxyproline residue O-arylated with a substituted quinolone group. 251 (BMS-605339) has a

the tumor-specific, Her2-binding IgG trastuzumab (Herceptin), using strain-promoted azide−alkyne cycloaddition.189 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 with 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 tumor 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 maximize 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 10826



Perspective

Scheme 29. Unusual Amino Acids in Peptidomimetics

Cyclic peptidomimetics for other indications have been developed (Scheme 29). Atanavir (264)212 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 the 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. 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 core unit consisting of an N-alkylated decahydroisoquinoline-3-carboxylic acid, fully reduced Tic.215 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 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 tripeptidelike 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

similar structure, with a publication describing its derivation from hexapeptide Ac-Asp-Glu-Nva-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 synthetic approaches to a complex unusual amino acid was recently reported for vinyl-ACC, a component of many HCV protease inhibitors.202 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 O-arylated 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 related complex structures have been reported in the references cited above and in many other publications and patents. 10827



Perspective

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 optimization programs. This perspective was written to provide an overview of the array of functionality presented by unusual amino acids, and to 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).223 Promiscuity and off-target toxicity are reduced with increased Fsp3 and number of chiral centers (48% decrease in promiscuity for nonaminergic compounds and 59% for aminergic compounds when the 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 derivatized 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).224,225 In one study, the reactions generally used to incorporate/ functionalize amino acids (amide and sulfonamide condensations and alkylations) accounted for 34% of all reactions,224 while in a larger study the acylation (22%) and N-alkylation/ arylation (18%) reactions comprised 40% of the total.225 Amino acids are unique building blocks in that they are found in all three major classes of drugs: 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 focuses 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 favoring 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 (MW < 500 Da) and protein (biological) therapeutics (MW > 5000 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

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 natural products that it is difficult to notice their presence (Scheme 30). Inhibitors of tryptophan Scheme 30. Unusual Amino Acids in Small Molecules

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 arylsubstituted 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, to combat laryngitis, and as a bronchial anti-inflammatory agent,222 and the compound is based around an O-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. 10828



Perspective

phosphatase 1B; Tba, tert-butylalanine; Tle, tert-leucine; Tic, tetrahydro-isoquinoline-3-carboxylic acid; TPH1, tryptophan hydroxylase-1

on enhancing their membrane permeability, reducing microsomal and proteolytic metabolism, and reducing their often high clearance rates. For example, recent studies have proposed general principles to improve peptide stability, potency, and oral bioavailability by steric inhibition,129 cyclization,90 N-methylation,3,226 and cyclic peptide scaffold design.227 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 increasingly large pool of available 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 Discovery Today 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 UAG-encoded residue in the structure of a methanogen methyltransferase. Science 2002, 296, 1462−1466. (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. 1987, 10, 265−272. (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 agonistbound 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 1-fluorocyclopropane-1carboxylate derivatives: En route to mglur 2 receptor agonist mgs0028. Org. Lett. 2004, 6, 3775−3777. (15) 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.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone +61-7-3346-2994. Notes

The author declares the following competing financial interest(s): 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. Biography 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 Ph.D., developing a useful route to functionalize 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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ABBREVIATIONS USED Aib, α-aminoisobutyric acid; 2,3-methano-Phe, 2-Ph-ACC, 1amino-2-phenylcyclopropane-1-carboxylic acid; DABA, 2,3diaminobutyric acid; Dap, 2,3-diaminopropionic acid; Dab, 2,4-diaminobutyric acid; DAP, 2,6-diaminopimelic acid; AMMA, 2-amino-2-3-(hydroxy-5-methylisoxazol-4-yl)acetic acid; AMPA, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid; Abu, 2-aminobutyric acid; Aoc, 2-azabicyclo[3.3.0]octane-3-carboxylic acid; Dopa, 3,4-dihydroxyphenylalanine; F2Pmp, 4′-phosphonodifluoromethyl-Phe; Pmp, 4′-phosphonomethyl-Phe; Adg, adamantylglycine; ACTH, adrenocorticotropic hormone; ACE, angiotensin-converting enzyme; BNCT, boron neutron capture therapy; CNS, central nervous system; Cha, cyclohexylalanine; Chg, cyclohexylglycine; Cpa, cyclopropylalanine; CsA, cyclosporine A; DGAT1, diacylglycerol acyltransferases; FSH-RH, follicle-stimulating hormone-releasing hormone; FFA2, free fatty acid receptor 2; GLP-1, glucagon-like peptide-1; GnRH, gonadotropin-releasing hormone; LFA-1, integrin leukocyte function associated antigen 1; JAK3, Janus tyrosine kinase 3; LHRH, luteinizing hormone-releasing hormone; nAChR, nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartic acid; Nle, norleucine; Nva, norvaline; Oic, octahydroindole-2-carboxylic acid; FOMT, O-fluoromalonyl Tyr; OMT, O-malonyl Tyr; Orn, ornithine; BPA, p-boronophenylalanine; Phg, phenylglycine; Phg, phenylglycine; pTyr, phospho-Tyr; PTP-1B, protein tyrosine 10829



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