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Literature DB >> 24900233

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

Bradley P Morgan¹, Alexander Muci¹, Pu-Ping Lu¹, Xiangping Qian¹, Todd Tochimoto¹, Whitney W Smith¹, Marc Garard¹, Erica Kraynack¹, Scott Collibee¹, Ion Suehiro¹, Adam Tomasi¹, S Corey Valdez¹, Wenyue Wang¹, Hong Jiang¹, James Hartman¹, Hector M Rodriguez¹, Raja Kawas¹, Sheila Sylvester¹, Kathleen A Elias¹, Guillermo Godinez¹, Kenneth Lee¹, Robert Anderson¹, Sandra Sueoka¹, Donghong Xu¹, Zhengping Wang¹, Nebojsa Djordjevic¹, Fady I Malik¹, David J Morgans¹.

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.

Entities: Disease Gene

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

Year: 2010 PMID： 24900233 PMCID： PMC4007828 DOI： 10.1021/ml100138q

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

16 in total

1. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.

Authors: R S Obach
Journal: Drug Metab Dispos Date: 1999-11 Impact factor: 3.922

Review 2. High-performance affinity chromatography: a powerful tool for studying serum protein binding.

Authors: David S Hage
Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2002-02-25 Impact factor: 3.205

3. 6-Chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]- indoline (SB-242084): the first selective and brain penetrant 5-HT2C receptor antagonist.

Authors: S M Bromidge; M Duckworth; I T Forbes; P Ham; F D King; K M Thewlis; F E Blaney; C B Naylor; T P Blackburn; G A Kennett; M D Wood; S E Clarke
Journal: J Med Chem Date: 1997-10-24 Impact factor: 7.446

4. Chromatographic analysis of carbamazepine binding to human serum albumin. II. Comparison of the Schiff base and N-hydroxysuccinimide immobilization methods.

Authors: Hee Seung Kim; Rangan Mallik; David S Hage
Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2006-05-09 Impact factor: 3.205

5. Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

Authors: S M Bromidge; S Dabbs; D T Davies; S Davies; D M Duckworth; I T Forbes; L M Gaster; P Ham; G E Jones; F D King; K R Mulholland; D V Saunders; P A Wyman; F E Blaney; S E Clarke; T P Blackburn; V Holland; G A Kennett; S Lightowler; D N Middlemiss; B Trail; G J Riley; M D Wood
Journal: J Med Chem Date: 2000-03-23 Impact factor: 7.446

6. Chromatographic analysis of carbamazepine binding to human serum albumin.

Authors: Hee Seung Kim; David S Hage
Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2005-02-25 Impact factor: 3.205

7. Synthesis and structure-activity relationships of trisubstituted phenyl urea derivatives as neuropeptide Y5 receptor antagonists.

Authors: C Fotsch; J D Sonnenberg; N Chen; C Hale; W Karbon; M H Norman
Journal: J Med Chem Date: 2001-07-05 Impact factor: 7.446

8. Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure.

Authors: You-Tang Shen; Fady I Malik; Xin Zhao; Christophe Depre; Sunil K Dhar; Patricio Abarzúa; David J Morgans; Stephen F Vatner
Journal: Circ Heart Fail Date: 2010-05-24 Impact factor: 8.790

9. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

Authors: M Packer; J R Carver; R J Rodeheffer; R J Ivanhoe; R DiBianco; S M Zeldis; G H Hendrix; W J Bommer; U Elkayam; M L Kukin
Journal: N Engl J Med Date: 1991-11-21 Impact factor: 91.245

10. The hydrolysis of amides and the proficiency of amidohydrolases. The burden borne by kw.

Authors: Guillermina Estiu; Kenneth M Merz
Journal: J Phys Chem B Date: 2007-05-18 Impact factor: 2.991

31 in total

1. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Authors: Fady I Malik; James J Hartman; Kathleen A Elias; Bradley P Morgan; Hector Rodriguez; Katjusa Brejc; Robert L Anderson; Sandra H Sueoka; Kenneth H Lee; Jeffrey T Finer; Roman Sakowicz; Ramesh Baliga; David R Cox; Marc Garard; Guillermo Godinez; Raja Kawas; Erica Kraynack; David Lenzi; Pu Ping Lu; Alexander Muci; Congrong Niu; Xiangping Qian; Daniel W Pierce; Maria Pokrovskii; Ion Suehiro; Sheila Sylvester; Todd Tochimoto; Corey Valdez; Wenyue Wang; Tatsuo Katori; David A Kass; You-Tang Shen; Stephen F Vatner; David J Morgans
Journal: Science Date: 2011-03-18 Impact factor: 47.728

2. Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions.

Authors: Simon Breitler; Nathan J Oldenhuis; Brett P Fors; Stephen L Buchwald
Journal: Org Lett Date: 2011-05-23 Impact factor: 6.005

Review 3. Leveraging Signaling Pathways to Treat Heart Failure With Reduced Ejection Fraction.

Authors: Miguel Pinilla-Vera; Virginia S Hahn; David A Kass
Journal: Circ Res Date: 2019-05-24 Impact factor: 17.367

4. A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors.

Authors: Laszlo Radnai; Rebecca F Stremel; James R Sellers; Gavin Rumbaugh; Courtney A Miller
Journal: J Vis Exp Date: 2019-08-17 Impact factor: 1.355

Review 5. Novel drug mechanisms in development for heart failure.

Authors: Soidjon D Khodjaev; John R Teerlink; Fady I Malik
Journal: Pflugers Arch Date: 2014-05-06 Impact factor: 3.657

6. Palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate: a practical synthesis of unsymmetrical ureas.

Authors: Ekaterina V Vinogradova; Brett P Fors; Stephen L Buchwald
Journal: J Am Chem Soc Date: 2012-06-29 Impact factor: 15.419