| Candidate ID: | R1551 |
| Source ID: | DB15011 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
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| Compound Name: |
Avacopan
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| Synonyms: |
Avacopan
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| Molecular Formula: |
C33H35F4N3O2
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| SMILES: |
CC1=CC=C(NC(=O)[C@H]2CCCN([C@H]2C2=CC=C(NC3CCCC3)C=C2)C(=O)C2=C(F)C=CC=C2C)C=C1C(F)(F)F
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| Structure: |
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| DrugBank Description: |
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.
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| CAS Number: |
1346623-17-3
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| Molecular Weight: |
581.656
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| DrugBank 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.
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| DrugBank 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.
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| DrugBank MoA: |
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<sub>H</sub>17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), 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 Fcγ 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<sup>+</sup> 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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| Targets: |
C5a anaphylatoxin chemotactic receptor 1 antagonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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