Revefenacin

A novel potent, long-acting, lung-selective inhaled muscarinic antagonist that has high affinity at M3 receptor, demonstrates in vitro kinetic selectivity for M3 over M2 and no meaningful off-target activity; produces sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours along with tiotropium and glycopyrronium, has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases.COPD Phase 3 Clinical (In Vitro) :The Kis of revefenacin are 0.42, 0.32, 0.18, 0.56, and 6.7 nM at human M1, M2, M3, M4 and M5 receptors, respectively. In a functional assay, revefenacin is shown to be a functional antagonist with inhibition constants similar to binding Ki's. Revefenacin also inhibits agonist-induced contraction of guinea pig isolated tracheal ring preparation with an affinity of 0.1 nM, similar to the measured M3 biding Ki. (In Vivo) :In anesthetized dogs, revefenacin, along with tiotropium and glycopyrronium, produce sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled revefenacin exhibits dose-dependent 24-hour bronchoprotection against methacholine-induced bronchoconstriction. The estimated 24-hour potency is 45.0 μg/mL and the bronchoprotective potencies are maintained after 7 days of once-daily dosing.