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Avacopan

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Chemistry

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Also known as: 1346623-17-3, Ccx168, Avacopan [inn], Avacopan [usan], Ccx-168, O880nm097t

Molecular Formula

C₃₃H₃₅F₄N₃O₂

Molecular Weight

581.6 g/mol

InChI Key

PUKBOVABABRILL-YZNIXAGQSA-N

FDA UNII

O880NM097T

Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is a rare (estimated incidence of 3 cases per 100,000 per year) form of "pauci-immune" systemic small-vessel vasculitis typified by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Despite complex pathophysiology, studies over the past ~2 decades have identified a key role for the alternative complement pathway and, in particular, the interaction between the anaphylatoxin fragment C5a and its cognate C5aR receptor in AAV. Avacopan (formerly CCX168) is an allosteric C5aR antagonist indicated for use in AAV. Avacopan was granted FDA approval on October 8, 2021, and is currently marketed under the name TAVNEOS by ChemoCentryx, Inc.

Avacopan is a Complement 5a Receptor Antagonist. The mechanism of action of avacopan is as a Complement 5a Receptor Antagonist, and Cytochrome P450 3A4 Inhibitor.

1 2D Structure

Avacopan

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

2.1.2 InChI

InChI=1S/C33H35F4N3O2/c1-20-12-15-25(19-27(20)33(35,36)37)39-31(41)26-10-6-18-40(32(42)29-21(2)7-5-11-28(29)34)30(26)22-13-16-24(17-14-22)38-23-8-3-4-9-23/h5,7,11-17,19,23,26,30,38H,3-4,6,8-10,18H2,1-2H3,(H,39,41)/t26-,30-/m0/s1

2.1.3 InChI Key

PUKBOVABABRILL-YZNIXAGQSA-N

2.1.4 Canonical SMILES

CC1=C(C(=CC=C1)F)C(=O)N2CCCC(C2C3=CC=C(C=C3)NC4CCCC4)C(=O)NC5=CC(=C(C=C5)C)C(F)(F)F

2.1.5 Isomeric SMILES

CC1=C(C(=CC=C1)F)C(=O)N2CCC[C@@H]([C@@H]2C3=CC=C(C=C3)NC4CCCC4)C(=O)NC5=CC(=C(C=C5)C)C(F)(F)F

2.2 Other Identifiers

2.2.1 UNII

O880NM097T

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Ccx168

2.3.2 Depositor-Supplied Synonyms

1. 1346623-17-3

2. Ccx168

3. Avacopan [inn]

4. Avacopan [usan]

5. Ccx-168

6. O880nm097t

7. (2r,3s)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-n-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide

8. (2r,3s)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-n-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

9. Tavneos

10. 3-piperidinecarboxamide, 2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-n-(4-methyl-3-(trifluoromethyl)phenyl)-, (2r,3s)-

11. Ccx168; Avacopan

12. Avacopan [jan]

13. Avacopan [usan:inn]

14. Avacopan [who-dd]

15. Avacopan (jan/usan/inn)

16. Unii-o880nm097t

17. Avacopan [orange Book]

18. Gtpl9450

19. Schembl2567144

20. Chembl3989871

21. C33h35f4n3o2

22. Dtxsid701102660

23. Ex-a2605

24. Mfcd28502293

25. At30195

26. Cs-6888

27. Db15011

28. Ac-35654

29. Hy-17627

30. J3.663.585a

31. D11093

32. Q27285470

33. (2r,3s)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-n-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

34. (2r,3s)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzene-1-carbonyl)-n-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

35. (2r,3s)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-n-[4-methyl-3-(trifluoromethyl)phenyl]-3-piperidinecarboxamide

36. Efd

2.4 Create Date

2011-01-24

3 Chemical and Physical Properties

Molecular Formula	C₃₃H₃₅F₄N₃O₂
Molecular Weight	581.6 g/mol
XLogP3	7.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Exact Mass	581.26654002 g/mol
Monoisotopic Mass	581.26654002 g/mol
Topological Polar Surface Area	61.4 Å²
Heavy Atom Count	42
Formal Charge	0
Complexity	918
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Avacopan is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis; GPA/MPA) in combination with standard therapy including glucocorticoids. Avacopan does not eliminate the need for glucocorticoids.

Tavneos, in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. Avacopan has been associated with hypersensitivity reactions, including angioedema, and hepatotoxicity, as evidenced by elevated liver transaminases. Likely due to its effect on the complement pathway, avacopan has also been associated with hepatitis B virus reactivation and serious infections, which should be monitored for as appropriate.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

AVACOPAN

5.2.2 FDA UNII

O880NM097T

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

5.3 ATC Code

L04

5.4 Absorption, Distribution and Excretion

Absorption

In AAV patients receiving 30 mg avacopan twice daily, avacopan had a C_max of 349 169 ng/mL and an AUC_0-12hr of 3466 1921 ng\*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the C_max by ~8%, the AUC by ~72%, and delayed the T_max by four hours (from two hours).

Route of Elimination

Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered in urine.

Volume of Distribution

Avacopan has an apparent volume of distribution of 345 L.

Clearance

Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 L/h.

5.5 Metabolism/Metabolites

Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself.

5.6 Biological Half-Life

A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, respectively.

5.7 Mechanism of Action

Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is considered a "pauci-immune" form of systemic small-vessel vasculitis accompanied by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Of the various known ANCAs, the major antigens are myeloperoxidase (MPO) and proteinase 3 (PR3/myeloblastin). The pathophysiology giving rise to AAV is complex, though a working model has been proposed. An initial trigger, such as infection, causes differentiation of naive T cells into T_H17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g., TNF- and IL-1), which prime neutrophils. Concurrently, the anaphylatoxin C5a is produced through activation of the alternative complement pathway, which also primes neutrophils through binding to the C5a receptor (C5aR; CD88). Primed neutrophils undergo physiological changes, including upregulating the display of ANCA antigens on their surface. Circulating ANCAs bind to displayed ANCA antigens on the surface of neutrophils; simultaneously, the Fc region of these ANCAs is recognized by Fc receptors on other neutrophils, resulting in excessive neutrophil activation. Activated neutrophils form NETs (neutrophil extracellular traps), which induce tissue damage and vasculitis. MPO/PR3 in NETs induces further ANCA production through dendritic cell- and CD4⁺ T cell-mediated activation of B cells, further exacerbating the condition. A role for complement was not initially considered in AAV due to a lack of excessive complement or immunoglobulin deposition in AAV lesions. However, extensive molecular studies confirmed a significant role for the alternative complement pathway, acting through C3 and C5, in the pathogenesis of AAV. The C5a fragment, generated by C5 cleavage, can bind to both the C5aR and C5a-like receptor (C5L2) on the surface of neutrophils; C5aR binding is associated with AAV while C5L2 binding has a protective effect. As the alternative complement pathway is self-sustaining in the absence of down-regulation by specific proteins, it is likely a significant driver of AAV. Furthermore, neutrophils activated by C5a release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway leading to the production of more C5a in a vicious cycle. Avacopan (CCX168) is a specific C5aR receptor allosteric antagonist that inhibits C5a-mediated neutrophil activation both _in vitro_ and _in vivo_. By inhibiting the C5a/C5aR axis, avacopan should have minimal effects on the formation of the membrane attack complex (which includes C5b) and therefore little effect on the innate immune response in treated patients.

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