title: Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac Myosin.
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.
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Alexander
authors.initials: A
authors.lastname: Muci
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Pu-Ping
authors.initials: PP
authors.lastname: Lu
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Qian
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Todd
authors.initials: T
authors.lastname: Tochimoto
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Whitney W
authors.initials: WW
authors.lastname: Smith
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Marc
authors.initials: M
authors.lastname: Garard
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Erica
authors.initials: E
authors.lastname: Kraynack
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Scott
authors.initials: S
authors.lastname: Collibee
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Ion
authors.initials: I
authors.lastname: Suehiro
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Adam
authors.initials: A
authors.lastname: Tomasi
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: S Corey
authors.initials: SC
authors.lastname: Valdez
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Wang
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: James
authors.initials: J
authors.lastname: Hartman
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Hector M
authors.initials: HM
authors.lastname: Rodriguez
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Raja
authors.initials: R
authors.lastname: Kawas
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Sheila
authors.initials: S
authors.lastname: Sylvester
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Elias
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Godinez
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lee
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Robert
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sueoka
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Donghong
authors.initials: D
authors.lastname: Xu
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Djordjevic
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
keywords: Omecamtiv mecarbil; cardiac myosin; small molecule enzyme activator; systolic heart failure