Avacopan

Avacopan is an antagonist of the complement 5a₁ (C5a₁) receptor (IC₅₀ = 0.1 nM).¹ It is selective for C5a₁ over the C5a₂ receptor and chemokine-like receptor 2 (CMKLR2), also known as chemerin receptor 2 or GPR1 (IC₅₀s = >10,000 nM for both), as well as the C3a receptor, CMKLR1, and formyl peptide receptor 1 (FPR1; IC₅₀s = >10,000 nM for all), and over panels of 18 chemokine receptors (IC₅₀s = ≥6,700 nM for all), 54 other receptors at 10 µM, and five cytochrome P450 (CYP) isoforms (IC₅₀s = >10,000 nM for all). Avacopan (50 nM) reduces the migration of isolated cynomolgus monkey neutrophils. It also reduces C5a-induced increases in neutrophil cell surface levels of CD11b in whole blood isolated from mice with a knock-in of human C5AR1, the gene encoding the C5a₁ receptor, when used at concentrations of 10 and 100 nM or when administered at doses of 0.075 or 0.15 mg/kg. Formulations containing avacopan have been used in the adjunctive treatment of severe vasculitis associated with anti-neutrophil cytoplasmic autoantibodies (ANCA).

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1. Bekker, P., Dairaghi, D., Seitz, L., et al. Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical study. PLoS One 11(10), e0164646 (2016).