The significance of chirality in contemporary drug discovery-a mini review

Abstract

More than half of drugs are chiral compounds with their chirality determining their molecular interactions, ecofriendly environmental safety and efficacy. Overall nearly 90% of chiral compounds are marketed as racemates consisting of an equimolar mixture of two enantiomers. Despite having identical chemical structure and bonding, racemates function differently when exposed to chiral environments and demonstrate notable variances in biological properties such as pharmacology, toxicology, metabolism and pharmacokinetics, etc. Advancements in asymmetric synthesis in recent years have led to considerable interest in the development of single enantiomers of chiral drug molecules for medicinal chemistry settings. In this review, we want to compile examples of chiral medicines approved by the FDA in the years 2022 and 2023 with an emphasis on their synthesis along with information on chiral induction as well as enantiomeric excess.

Fig. 1. Few examples of FDA-approved chiral small-molecule drugs.

Fig. 2. The total number of biologic (blue) and small molecule (orange) NTEs approved by the FDA between 2020 and 2022.

Fig. 3. Methods of asymmetric synthesis.

Fig. 4. Few examples of structure of chiral drugs approved by FDA in 2000–2021.

Fig. 5. Structure of chiral drugs approved by FDA in 2022.

Fig. 6. Structure of chiral drugs approved by FDA in 2023.

Scheme 1. Synthesis of oteseconazole.

Scheme 2. Synthesis of daridorexant.

Scheme 3. Synthesis of abrocitinib.

Scheme 4. Synthesis of futibatinib.

Scheme 5. Synthesis of adagrasib.

Scheme 6. Synthesis of lenacapavir.

Scheme 7. Synthesis of olutasidenib.

Scheme 8. Synthesis of mavacamten.

Scheme 9. Synthesis of ganaxolone.

Scheme 10. Synthesis of sulbactam.

Scheme 11. Synthesis of fezolinetant.

Scheme 12. Synthesis of trofinetide.

Scheme 13. Synthesis of capivasertib.

Scheme 14. Synthesis of leniolisib.

Scheme 15. Synthesis of ritlecitinib.

Scheme 16. Synthesis of iptacopan.

Scheme 17. Synthesis of elacestrant.

Scheme 18. Synthesis of nirogacestat.

Scheme 19. Synthesis of pirtobrutinib.

Scheme 20. Synthesis of lotilaner.

Scheme 21. Synthesis of zavegepant.