Analysis of 70 macrocyclic drugs approved by the FDA

Physicians are constantly searching for innovative approaches to emerging diseases and areas of unmet clinical need. Macrocyclic small-molecule drugs, cyclic peptides, proteolysis-targeting chimeras (PROTACs), and oligonucleotides are prominent examples of novel drug modalities, many of which do not follow the criteria for an "ideal" oral formulation that follows Lipinski's five rules.

Recently, J.M Ed. Chem. Articles published in the latest MacrocyclesinDrugDiscovery - LearningfromthePastfortheFuture, analysis the characteristics of drug approved by FDA of macrocyclic compounds.

Macrocycles are usually defined as closed-loop organic molecules containing at least 12 heavy atoms, with heavy atoms referring to atoms other than H. General interest in macrocyclic compounds began to grow in different scientific fields in the late 1970s and surged from the 1990s (FIG. 1). In drug discovery, the phase of rapid growth began at the turn of the century (Figure 1).

The benefit of macrocyclic compounds is that they can provide functional diversity and stereochemical complexity in a semirigid, prefixed structure. Macrocyclic compounds have higher affinity and selectivity than their ring-opening analogues and can bind to targets that are difficult to deliver with conventional small-molecule drugs.

CyclosporineA (Figure 2), with a molecular weight as high as 1202Da, was the first oral formulation of the peptide. Historically, macrocyclic drugs have mostly been naturally occurring compounds (e.g., cyclosporine), but de novo macrocyclic drugs are also gaining regulatory approval in large numbers.

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Fda-approved macrocyclic drug analysis

To date, a total of 70 macrocyclic compounds have been approved by the FDA as drugs (Table 1), of which 28 (40%) were administered orally and 42 were administered parenteral. The vast majority of macrocyclic drugs are natural products or derivatives thereof (n=59,88%), and the first macrocyclic drug with a denovodesign (denovodesign), plerixafor, was not approved until 2008.

Analysis of natural products subdivided into original natural products (n=25) and natural product derivatives (n=34) revealed that 12 natural product derivatives were derived from pharmacokinetic optimization.

Following PK optimization, seven antimicrobial gibberellin and rifamycin derivatives, as well as everolimus for oncology and immunosuppressant, showed improved oral bioavailability and half-life. The chemical stability, protease tolerance, and solubility of the other three derivatives were improved. Pharmacodynamics, broader activity, and reduced side effects constitute the main reasons for the production of the seven derivatives. Five derivatives were optimized in both pharmacodynamics and pharmacokinetics.

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Indication and target analysis of macrocyclic drugs

Infectious diseases were the main indication for macrocyclic drug therapy (44.4% of all macrocyclic drugs, Figure 4, Table 1). In this category, most were used as antibacterial agents (29%), but antivirals (6.9%) and antifungals (8.3%) were also important. Tumors (20.8%), autoimmune diseases (5.6%) and immunosuppressants (5.6%) were the next three main indications. The total proportion of macrocyclic drugs used for 13 other minor indications was 23.6%, including antidiuretic, chronic pain, hereditary obesity, heart failure, etc.

Trends in macrocyclic drug approvals:

The frequency with which antimicrobial drugs have been approved since 1948 has been fairly regular;

Five macrocyclic compounds for the treatment of HCV infection were all approved between 2013 and 2017;

In recent years, the application of macrocyclic compounds in oncology has been greatly demonstrated. A total of 4 drugs were approved before 2007, and 11 drugs were approved after 2007.

In terms of the drug targets of macrocyclic compounds, it can be found that antibacterial macrocyclic compounds mainly target some "traditional" targets, such as ribosomes and RNA polymerase (RNAP). But in oncology, macrocyclic compounds target a wide range of targets including kinases, deacetylases, hormone receptors, and tubulin. Pacritinib(Figure 5) was approved in 2022 and is the first dual inhibitor of Janus kinase 2(JAK2) and Fms-like receptor tyrosine kinase 3(FLT3). Of note, the NS3/4A protease of hepatitis C virus is the only viral target regulated by macrocyclic drugs.

In addition to this, there are several macrocyclic drugs that act as molecular gums, forming ternary complexes with protein targets. "The combination of cyclosporine and wolrosporine with cyclophilin A(CyPA) and neurocalcin B(CNB) is used in the treatment of autoimmune diseases and in immunosuppression to prevent transplant organ rejection." Fk506-binding protein FKBP12 in ternary complexes with CNB or mammalian target of rapamycin (mTOR), induced by macroloops of ascomycin and the rapamycin family, is used in autoimmune diseases, immunosuppression, and oncology.

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Conclusion

Macrocyclic drugs are mainly used as antibacterial agents, and tumors are the second most common indication. A survey of the literature suggests that tumors will remain a major indication in the future, but macrocyclic compounds are also expected to be used for a variety of new indications. In addition, macrocyclic compounds are undergoing clinical trials or preclinical studies against a large number of different receptors.

Examination of the structure of macrocyclic drug-target binding complexes (n=34) revealed that 79% of macrocyclic drugs modulate those targets with flat, tunneled, or grooved binding sites. In the ternary complex, the macrocyclic drug acts as a molecular glue, occupying three groove-shaped binding sites. A comparison with a set of drugs that meet the criteria for Lipinski's five-rule concludes that macrocyclic compounds can modulate the targets of these hard-to-target drugs because macrocyclic compounds are more likely to adopt the dominant conformations of discs and spheroids. The crystal structures of the targets of only five clinical candidates have been disclosed. Three of these macrocyclic compounds are bound in the trough binding site and one in the tunnel binding site.

Among macrocyclic drugs and clinical candidates, natural products and their derivatives are far more numerous than de novo designed compounds (proportion> 4:1). Derivatives of natural products primarily improve pharmacokinetics, pharmacodynamics, or, in rare cases, both. Close to 40% of macrocyclic drugs have oral bioavailability, compared with approximately 30% of clinical candidates.

References:

[1] Doak, B.C.E tal. OralDruggableSpacebeyondtheRuleof5: InsightsfromDrugsandClinicalCandidates. Chem. Biol. 2014,21,1115-1142.

[2] schultz, M.D.T woDecadesundertheInfluenceoftheRuleofFiveandtheChangingPropertiesofApprovedOralDrugs. J.M Ed. Chem. 2019,62,1 701-1714.

[3] Jimenez, D.G.E tal. MacrocyclesinDrugDiscovery ─ LearningfromthePastfortheFuture.J.Med.Chem.2023.doi.org/10.1021/acs.jmedc hem.3c00134

[4]Marsault,E.etal.MacrocyclesAreGreatCycles:Applications,Opportunities,andChallengesofSyntheticMacrocyclesinDrugDiscove Ry. J.M Ed. Chem. 2011,54,1961-2004.

[5] Begnini, F.e tal. MiningNaturalProductsforMacrocyclestoDrugDifficultTargets. J.M Ed. Chem. 2021,64,1054-1072.

[6] DeLorbe, J.E.E tal. ThermodynamicandStructuralEffectsofMacrocyclicConstraintsinProtein - LigandInteractions. ACSMed. Chem. Le Tt. 2010,1,448-452.

[7]Giordanetto,F.etal.MacrocyclicDrugsandClinicalCandidates:WhatCanMedicinalChemistsLearnfromTheirProperties? . J.M Ed. Chem. 2014,57,278-295.

[8] Shawky, A.M.etal.Com prehensiveOverviewofGloballyApprovedJAKInhibitors. Pharmaceutics. 2022,14,1001,

[9] Schreiber, S.L.T heRiseofMolecularGlues. Cell. 2021184, 3-9.