Characterization of a Long Acting Smooth Muscle Myosin Inhibitor, CK‐2125927, as a Novel Therapeutic Mechanism for Bronchodilation

Abstract

Listen

Translate article

Smooth muscle myosin is a mechanochemical enzyme that hydrolyzes ATP to generate mechanical force; ultimately all signaling pathways that modulate smooth muscle tone converge on the regulation of this motor protein. We previously showed that a novel smooth muscle myosin inhibitor, CK‐2019165, inhibited the methacholine‐induced bronchoconstriction in rat models with a short duration of action (~ 2 hours). Here we describe the discovery and characterization of a long acting smooth muscle myosin inhibitor for bronchodilation. Using high throughput screening, we identified and subsequently optimized a class of selective inhibitors of smooth muscle myosin. These compounds potently inhibit the smooth muscle myosin ATPase (IC50≤ 30 nM). An optimized member of this series, CK‐2125927,, inhibited calcium‐induced contraction of skinned rat tail artery in a concentration dependent manner with an IC50 of ~ 1 μM. CK‐2125927 induced concentration‐dependent relaxation of methacholine‐pre‐constricted rat tracheal rings with an EC50 of ~ 1 μM. Further, CK‐2125927 (10 μM) completely inhibited electrical field stimulation‐induced constriction of guinea pig tracheal rings with a 50% recovery time of > 6 hours, a duration comparable to the long‐acting beta‐adrenergic agonist salmeterol. Together these data suggest CK‐2125927 is a long‐acting smooth muscle myosin inhibitor that may provide a novel therapeutic approach for the treatment of diseases where bronchoconstriction plays a role, such as asthma and COPD.