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Characterization of a Long Acting Smooth Muscle Myosin Inhibitor, CK‐2125927, as a Novel Therapeutic Mechanism for Bronchodilation
Author(s) -
Pannirselvam Malar,
Jia Zhiheng,
Durham Nickie,
Zavodovskaya Marianna,
Lenzi David,
Clancy Sheila,
Hartman James J,
Morgans David J,
Morgan Bradley P,
Qian Xiangping,
Malik Fady I
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1020.6
Subject(s) - bronchodilation , myosin light chain kinase , bronchoconstriction , myosin , methacholine , chemistry , contraction (grammar) , muscle contraction , medicine , muscle relaxation , endocrinology , biophysics , pharmacology , biochemistry , biology , bronchodilator , lung , asthma , respiratory disease
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 (IC 50 ≤ 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 IC 50 of ~ 1 μM. CK‐2125927 induced concentration‐dependent relaxation of methacholine‐pre‐constricted rat tracheal rings with an EC 50 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.