Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac Myosin

  • ACS Med Chem Lett. 2010 Aug 20;1(9):472-7. doi: 10.1021/ml100138q.
Bradley P Morgan  1 ,  Alexander Muci  1 ,  Pu-Ping Lu  1 ,  Xiangping Qian  1 ,  Todd Tochimoto  1 ,  Whitney W Smith  1 ,  Marc Garard  1 ,  Erica Kraynack  1 ,  Scott Collibee  1 ,  Ion Suehiro  1 ,  Adam Tomasi  1 ,  S Corey Valdez  1 ,  Wenyue Wang  1 ,  Hong Jiang  1 ,  James Hartman  1 ,  Hector M Rodriguez  1 ,  Raja Kawas  1 ,  Sheila Sylvester  1 ,  Kathleen A Elias  1 ,  Guillermo Godinez  1 ,  Kenneth Lee  1 ,  Robert Anderson  1 ,  Sandra Sueoka  1 ,  Donghong Xu  1 ,  Zhengping Wang  1 ,  Nebojsa Djordjevic  1 ,  Fady I Malik  1 ,  David J Morgans Jr  1
Affiliations
  • 1. Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
PMID: 24900233 DOI: 10.1021/ml100138q
Abstract

We report the design, synthesis, and optimization of the first, selective activators of cardiac Myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble Myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.

Keywords
Omecamtiv mecarbil; cardiac myosin; small molecule enzyme activator; systolic heart failure.
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