Rimegepant

Rimegepant (BMS-927711) is an orally bioavailable and blood-brain barrier permeable antagonist of CGRP and AMY1 receptors, with a pIC₅₀ of 8.01 and a K_i of 0.027 nM for human CGRP receptors. Rimegepant antagonizes cAMP production induced by αCGRP, βCGRP and amylin at CGRP and AMY1 receptors in humans, rats and mice, as well as at rat AMY3 receptors. Rimegepant can be used in research related to migraine^[1]. In Vitro:Rimegepant (10 μM; 15 min) antagonizes cAMP production at rat CGRP, AMY₁, and AMY₃ receptors with apparent pA₂ values of 6.41, 6.43-5.73, and 6.45 respectively, but shows no quantifiable activity at other rat calcitonin family receptors^[1].
Rimegepant (10 μM; 15 min) antagonizes cAMP production at mouse CGRP receptors with an apparent pA₂ of 6.89, shows weak, inconsistent activity at mouse AMY₁ receptors, and has no quantifiable activity at other mouse calcitonin family receptors^[1].
Rimegepant (tested across a concentration range; 15 min) inhibits cAMP production at human CGRP receptors with a pIC₅₀ of 8.01, and at human AMY₁ receptors with pIC₅₀ values of 6.25 (human-αCGRP agonist) and 5.66 (human-amylin agonist)^[1].
Rimegepant (tested at concentrations enabling apparent pA₂ determination; 15 min) antagonizes cAMP production at human CGRP receptors with apparent pA₂ values of 9.56 (human-αCGRP) and 9.34 (human-βCGRP), and at human AMY₁ receptors with apparent pA₂ values of 8.07 (human-αCGRP) and 7.48 (human-amylin), but shows no quantifiable activity at human AM₁ or AM₂ receptors^[1].
Rimegepant (compound 8) potently binds to the human CGRP receptor in SK-N-MC cell membranes with a K_i of 0.027 nM and a protein-adjusted K_i of 0.39 nM^[2].
Rimegepant acts as a full, competitive antagonist of CGRP-stimulated cAMP production in SK-N-MC cells with an IC₅₀ of 0.14 nM^[2].
Rimegepant (BMS-927711/compound 8) has improved human liver microsomal stability with a half-life of 83 min^[2].
Rimegepant shows low inhibition of human CYP isoforms, with an IC₅₀ of 17 μM for CYP3A4 and IC₅₀ ≥20 μM for all other tested isoforms^[2].
Rimegepant exhibits no significant off-target liabilities in a panel of 45 receptor, ion channel binding, and enzyme activity assays^[2].
Rimegepant (10-30 μM) causes less than 30% inhibition of the hERG potassium channel at 10 and 30 μM and has no significant effect on L-type sodium or calcium channels in HEK-293 cells^[2]. In Vivo:Rimegepant (12.84 mg/kg; p.o.; single dose, daily for 7 days) administered orally at 12.84 mg/kg reaches measurable contents in mouse plasma, dura mater, TG, parietal brain cortex, and hypothalamus, with peak tissue levels at 3 hours post-single dose, and shows only minimal accumulation in the parietal brain cortex with chronic daily dosing^[3].