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Review
. 2021 Aug 10;12(10):1650-1671.
doi: 10.1039/d1md00131k. eCollection 2021 Oct 20.

Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies

Xi Wang  1 , Yuanxun Wang  2 , Xuemin Li  1 , Zhenyang Yu  1 , Chun Song  3 , Yunfei Du  1
Affiliations
Review

Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies

Xi Wang et al. RSC Med Chem. .

Abstract

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. The number of nitrile-containing drugs approved by the FDA from 2010 to 2020.
Fig. 2
Fig. 2. The structures of cromakalim (1) and its derivatives.
Fig. 3
Fig. 3. The structure of donitriptan (8).
Fig. 4
Fig. 4. The structures of verapamil (9) and its derivatives.
Fig. 5
Fig. 5. The structure of milrinone (12).
Fig. 6
Fig. 6. (a) The structure of berotralstat (13). (b) The molecular mechanism of action of berotralstat (13). FXII: factor XII; FXIIa: factor XIIa; C1 INH: complement 1 inhibitor.
Fig. 7
Fig. 7. The structures of nonsteroidal androgen receptor antagonists.
Fig. 8
Fig. 8. The structures of nonsteroidal aromatase inhibitors.
Fig. 9
Fig. 9. The structures of neratinib (22) and pyrotinib (23).
Fig. 10
Fig. 10. The structure of osilodrostat (24).
Fig. 11
Fig. 11. The structures of dipeptidyl peptidase IV inhibitors.
Fig. 12
Fig. 12. The structure of bosutinib (28).
Fig. 13
Fig. 13. The structure of glasdegib (29).
Fig. 14
Fig. 14. The structures of ivosidenib (30) and its derivative (31).
Fig. 15
Fig. 15. The structures of Janus kinase inhibitors.
Fig. 16
Fig. 16. The structure of ozanimod (35).
Fig. 17
Fig. 17. The structure of cilomilast (36).
Fig. 18
Fig. 18. The metabolic conversion from leflunomide (37) to (Z)-teriflunomide (38) and (E)-teriflunomide (38).
Fig. 19
Fig. 19. The left panel shows the structures of febuxostat (39) and topiroxostat (40); the right panel shows the hypoxanthine metabolism catalyzed by XOR. XO: xanthine oxidase; XDH: xanthine dehydrogenase; NAD+: nicotinamide adenine dinucleotide; NADPH: dihydronicotinamide adenine dinucleotide.
Fig. 20
Fig. 20. The structure of dienogest (41).
Fig. 21
Fig. 21. The structures of crisaborole (42), AN2898 (43), and 44.
Fig. 22
Fig. 22. The structure of cefmetazole (45).
Fig. 23
Fig. 23. The structures of finafloxacin (46) and pradofloxacin (47).
Fig. 24
Fig. 24. The structures of isavuconazole (48), ravuconazole (50) and their derivatives.
Fig. 25
Fig. 25. The structures of luliconazole (52) and lanoconazole (53).
Fig. 26
Fig. 26. The structures of non-nucleoside reverse transcriptase inhibitors.
Fig. 27
Fig. 27. The structures of remdesivir (57) and its active metabolite (58).
Fig. 28
Fig. 28. The structure of (S)-citalopram (59).
Fig. 29
Fig. 29. The structure of vilazodone (60).
Fig. 30
Fig. 30. The structure of cyamemazine (61).
Fig. 31
Fig. 31. The structure of entacapone (62).
Fig. 32
Fig. 32. The structure of perampanel (63) and other candidates.
Fig. 33
Fig. 33. The structures of alectinib (66) and lorlatinib (67).
Fig. 34
Fig. 34. The structure of selpercatinib (68).
Fig. 35
Fig. 35. The structures of cimetidine (69) and metiamide (70).
Fig. 36
Fig. 36. The structure of vitamin B12 (71).
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