873697-70-2Relevant articles and documents
Development of a Factory Process for Omecamtiv Mecarbil, a Novel Cardiac Myosin Activator
Caille, Seb,Allgeier, Alan M.,Bernard, Charles,Correll, Tiffany L.,Cosbie, Andrew,Crockett, Richard D.,Cui, Sheng,Faul, Margaret M.,Hansen, Karl B.,Huggins, Seth,Langille, Neil,Mennen, Steven M.,Morgan, Bradley P.,Morrison, Henry,Muci, Alexander,Nagapudi, Karthik,Quasdorf, Kyle,Ranganathan, Krishnakumar,Roosen, Philipp,Shi, Xianqing,Thiel, Oliver R.,Wang, Fang,Tvetan, Justin T.,Woo, Jacqueline C. S.,Wu, Steven,Walker, Shawn D.
, p. 1558 - 1567 (2019/09/04)
The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5-phosphate. Overall, the longest linear sequence consists of six steps, including a final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modified-release formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturability.
HETEROCYCLIC COMPOUNDS AND THEIR USES
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, (2014/10/04)
Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.
Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac myosin
Morgan, Bradley P.,Muci, Alexander,Lu, Pu-Ping,Qian, Xiangping,Tochimoto, Todd,Smith, Whitney W.,Garard, Marc,Kraynack, Erica,Collibee, Scott,Suehiro, Ion,Tomasi, Adam,Valdez, S. Corey,Wang, Wenyue,Jiang, Hong,Hartman, James,Rodriguez, Hector M.,Kawas, Raja,Sylvester, Sheila,Elias, Kathleen A.,Godinez, Guillermo,Lee, Kenneth,Anderson, Robert,Sueoka, Sandra,Xu, Donghong,Wang, Zhengping,Djordjevic, Nebojsa,Malik, Fady I.,Morgans, David J.
, p. 472 - 477 (2011/03/20)
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.
