Macrocyclic Drugs and Clinical Candidates: What Can Medicinal

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Macrocyclic drugs and clinical candidates – what can medicinal chemists learn from their properties Fabrizio Giordanetto, and Jan Kihlberg J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm400887j • Publication Date (Web): 28 Aug 2013 Downloaded from http://pubs.acs.org on August 31, 2013

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Journal of Medicinal Chemistry

Macrocyclic drugs and clinical candidates – what can medicinal chemists learn from their properties Fabrizio Giordanetto*# and Jan Kihlberg*€

Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

ABSTRACT Macrocycles are ideal in efforts to tackle ¨difficult¨ targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates, revealed that macrocycles are predominantly used for infectious disease and in oncology, and that the majority belong to the macrolide or cyclic peptide classes. A significant number (N=34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging towards 250 Å2. Moreover, insight from a group of ¨de novo designed¨ oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes, may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers, or if macrocycles will open up novel oral druggable space.

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1. INTRODUCTION It has proven to be extremely difficult to develop small molecule probes and drugs against targets with extended binding sites, i.e. class B G-protein coupled receptors (GPCRs), proteinprotein interactions and some enzymes.1 Currently ¨biologics¨ therefore constitute the most common approach for modulation of these targets, with limitations such as high cost, reduced patient compliance, lack of cellular penetration and low oral bioavailability. One reason for these difficulties could be that small molecule hits and leads that are compliant with Lipinski’s rule-of5 have been sought for to increase the likelihood of obtaining favorable physicochemical and pharmacokinetic properties,2 and in order to reduce risks of compound related toxicity.3, 4 However, by stepping slightly outside rule-of-5 chemical space, compound diversity and opportunities to develop probes and drugs against ¨difficult¨ targets can be enhanced. Macrocycles have several features that make them interesting in efforts to tackle ¨difficult¨ targets with extended binding sites.5, 6 Because of their size and complexity they can engage targets through numerous and spatially distributed binding interactions, thereby increasing both binding affinity and selectivity. Furthermore, cyclisation provides a degree of structural preorganisation that may reduce the entropy cost of receptor binding as compared to linear analogues.5, 7 It should, however, be pointed out that macrocycles are not completely rigid. Instead they may offer a suitable compromise between pre-organisation and sufficient flexibility that could facilitate interactions with dynamic protein targets. In addition some reports suggest that cyclisation has a favorable impact on other essential properties required for drugs, such as membrane permeability,8 metabolic stability and overall pharmacokinetics.5, 6


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A significant number of macrocyclic drugs are currently on the market, predominantly of natural product origin with complex structures. Concerns that synthetic tractability will limit opportunities for lead optimization and increase costs for scale up is one reason why the pharmaceutical industry has been cautious about development of macrocyclic drugs. This concern has resulted in that macrocycles have been excluded from most academic and industry screening collections; for example the AstraZeneca high throughput screening (HTS) collection contains 12 atoms) that are marketed today for human use, and their associated data consisting of chemical information, pharmacokinetics, pharmacology and results from clinical development were extracted. Biologics and proteins, defined as polypeptides with >30 amino acids, as well as contrast agents and veterinary drugs were removed from further analysis. This curation resulted in a dataset consisting of 68 macrocyclic drugs, which were further annotated with in silico molecular descriptors19 and information obtained from the literature on their route of administration,20 bioavailability and dose in humans (cf. Table S1 in the Supporting Information for structures, indication, physical chemical properties, etc.). A dataset of 35 macrocycles currently in clinical development was obtained in an analogous manner by mining of Adis R&D Insight,21 and the literature, followed by curation and annotation just as for the set of marketed drugs (cf. Table S2 in the Supporting Information for structures, indication, physical chemical properties, etc.). In addition, compounds for which structures were not available were excluded from the latter dataset. Through these


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efforts we have striven to make the two datasets of macrocycles as complete and accurate as possible. As information on launched drugs is readily available we assume that the dataset of marketed macrocyclic drugs is essentially complete. In contrast, the dataset of macrocycles in clinical development is most likely less complete because some companies do not disclose structures, in particular for compounds in phase I but also in phase II studies. 3. CLASSIFICATION AND PROPERTIES OF MARKETED MACROCYCLIC DRUGS 3.1 General characteristics of macrocyclic drugs. Inspection of the 68 macrocyclic drugs on the market revealed that half of them are used to treat infections (Figure 1a). Most of these are used for infections of bacterial origin and a few are for parasites or fungi. Oncology is the second largest therapeutic area, with one out of seven macrocycles being applied for treatment of various types of cancer. A few macrocyclic drugs are employed for managing cardiovascular disease (heart failure, thrombosis, acute coronary syndrome and hypertension), as well as in gynaecology (fertility, induction or inhibition of labor) and immunology (immunosuppression to prevent transplant rejection). The remainder of the macrocyclic drugs have found use in indications ranging from anesthesiology to pain. The majority of the macrocyclic drugs were distributed almost equally between only two chemical classes; cyclic peptides and macrolides (Figure 1b). The cyclic peptides are delivered parenterally, with the exception of cyclosporin A. The macrolide class, however, contains 15 macrocyclic drugs that allow oral administration as well as an additional nine macrolides that are administered parenterally. Of the remaining macrocycles, a few belong to the ansamycin and porphyrin classes, while the alkaloid, bicyclam, cyclodextrin and epothilone classes each have one macrocyclic drug member. Three out of the four registered ansamycins are administered


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orally to patients, while the macrocycles from the remaining five minor classes all are parenterals. Thus, oral macrocycles predominantly originate from the macrolide class, with a few being ansamycins and one a cyclic peptide. In contrast, parenteral macrocycles span a much broader chemical space. Interestingly oral macrocyclic drugs serve just two indications, infection and immunology, while parenteral macrocycles find application in a wider range of therapeutic areas. A complete overview of the distribution of marketed macrocyclic drugs across indication and chemical classes is given in the supporting information (Table S1).

Figure 1. Distribution of oral (green bars, N=19) and parenteral (red bars, N=49) macrocyclic drugs across different therapeutic indications (a) and chemical classes (b). As mentioned above only 19 of the 68 macrocyclic drugs are administered orally, and 15 of these belong to the macrolide class (Figure 1b, green bars). As could be expected, a comparison of the calculated physical chemical properties of parenteral and oral macrocycles with oral small molecule drugs provides an explanation for the route of administration (Table 1). Parenteral macrocycles as a class are significantly more polar than either of the oral macrocycles or small molecule drugs. Thus, the parenterals have more hydrogen bond donors, and consequently larger polar surface areas, than the two classes of orals. The calculated lipophilicity (cLogP) is also


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significantly lower for the parenteral macrocycles than for either class of oral drugs. In addition, the mean molecular weight of the parenteral macrocycles is higher than for the oral macrocycles. Comparing the oral macrocycles with the oral small molecule drugs reveals that molecular weight, cLogP, polar surface area and number of hydrogen bond donors are on average ≥2 times higher for the oral macrocycles. A small number (N=89, 5.6 %) of the oral small molecule drugs have a molecular weight >500 and are not macrocyclic. A comparison of this subset with the oral macrocyclic drugs reveals that the polarity is lower (fewer hydrogen bond donors and smaller polar surface area) for the non-macrocyclic drug subset with molecular weight >500, that the lipophilicity is similar and that the macrocyclic drugs have a higher molecular weight. In conclusion, parenteral administration of macrocycles appears to be driven by the higher number of hydrogen bond donors displayed by this class than for macrocycles and small molecule drugs that are administered orally. Interestingly, even though relatively few oral macrocyclic drugs exist their molecular weight is indeed significantly higher than for oral small molecules, as well as the subset of non-macrocyclic drugs with molecular weight >500 (Table 1). Most likely, oral availability among macrocyclic drugs, and non-macrocyclic drugs with molecular weight >500, is facilitated by their relatively high lipophilicity as compared to the ¨average¨ oral small molecule drug.


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Table 1. Calculated physical chemical propertiesa for oral small molecule drugs, different classes of registered macrocycle drugs and

1 macrocycles in clinical development. 2 3 Route of Status Class 4 administration 5 6 Oral 7 Small molecule 8 Oral, MW>500 9 10 Oral 11 Macrocycle Parenteral 12 Registered 13 Oral 14 Cyclic peptide 15 Parenteral 16 17 Oral 18 Macrolide 19 Parenteral 20 21 Oral 22 Macrocycle 23 Parenteral 24 25 Oral 26 Cyclic peptide 27 Parenteral 28 Clinical development Oral 29 Macrolide 30 Parenteral 31 32 Oral 33 “de novo designed” 34 Parenteral 35 36 a Mean value (lower and upper margins of 95% confidence interval) 37 38 bHydrogen bond donors 39 40 cPolar surface area 41 42 dcalculated LogP 43 e 44 Molecular weight 45 46 47 48

N

HBDa,b

PSAa,c

cLogPa,d

MWa,e

1589

2 (2 – 2)

74 (71 – 76)

2.2 (2.1 – 2.4)

322 (317 – 328)

89

2 (2 – 3)

139 (127 – 152)

4.2 (3.7 – 4.9)

602 (582 – 624)

18

4 (3 – 5)

212 (200 – 225)

4.4 (3.0 – 5.8)

852 (805 – 901)

45

14 (11 – 17)

417 (347 – 488)

0.6 (-1.2 – 2.3)

1126 (996 – 1257)

1

5

290

14.4

1203

26

19 (15 – 22)

529 (444 – 614)

-0.8 (-3.0 – 1.4)

1294 (1128 – 1461)

14

4 (3 – 4)

205 (194 – 215)

3.7 (2.7 – 4.6)

831 (798 – 864)

9

6 (3 – 9)

240 (194 – 286)

2.1 (-1.2 – 5.5)

867 (771 – 963)

15

3 (2 – 4)

171 (130 – 214)

6.9 (5.3 – 8.5)

775 (634 – 916)

20

8 (5 – 11)

270 (189 – 351)

2.4 (0.5 – 4.2)

908 (751 – 1065)

3

5 (4 – 6)

277 (227 – 327)

11.3 (6.3 – 16.2)

1162 (946 – 1379)

8

15 (10 – 20)

450 (339 – 561)

-0.1 (-2.7 – 2.7)

1176 (936 – 1416)

2

3 (2 – 3)

203 (190 – 215)

5.2 (1.2 – 9.1)

911 (755 – 1067)

3

3 (2 – 4)

173 (87 – 260)

4.8 (0.9 – 8.8)

733 (402 – 1064)

9

2 (1 – 2)

121 (78 – 165)

5.7 (4.9 – 6.4)

598 (494 – 701)

1

4

173

6.1

937


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3.2 Properties of macrocyclic drugs in the cyclic peptide class. Exactly 30 of the macrocyclic drugs are cyclic peptides, which can be divided further into several subclasses (Figure 2, Table S1). The disulfide-bridged cyclic peptide subclass is the largest of these, with members such as argipressin and lanreotide. The glycopeptide subclass (e.g. vancomycin hydrochloride), the lipopeptide class of echinocandins (e.g. anidulafungin) and cyclic peptides with chemical modifications on amino acid side chains (e.g. pasireotide) each have three members, whereas the few remaining cyclic peptide drugs belong to six different subclasses. All macrocyclic peptide drugs except cyclosporin A, an N-methylated undecapeptide, are administered through various parenteral routes, in line with the general observation that insufficient oral bioavailability is a key limitation for peptide therapeutics. Inspection of the physical chemical properties of this set of parenteral cyclic peptide drugs shows that they are highly polar with a large number of hydrogen bond donors, a resulting large polar surface area and low cLogP (Table 1). The mean molecular weight is also high. Taken together the physical chemical properties of non-oral cyclic peptide drugs provide a clear rationale for why parenteral administration is required.


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Figure 2. Distribution of oral (green bar) and parenteral (red bars, N=29) macrocyclic peptide drugs across different sub-classes. As mentioned above cyclosporin A, is the only one of the marketed macrocyclic peptide drugs that is administered orally. However, absorption in the gastrointestinal tract is highly variable, resulting in that bioavailabilities range from

Macrocyclic Drugs and Clinical Candidates: What Can Medicinal

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