873697-71-3 Usage
Description
Omecamtiv mecarbil, also known as CK-1827452, is a specific cardiac myosin activator and a clinical drug for left ventricular systolic heart failure, currently in Phase 2 of development.
Used in Pharmaceutical Industry:
Omecamtiv mecarbil is used as a treatment for left ventricular systolic heart failure. It accelerates the transition of myosin into the force-generating state without affecting cardiac myocyte calcium homeostasis, thereby increasing cardiac function by increasing the duration of ejection without changing the rates of contraction.
In vitro
In vitro, Omecamtiv mecarbil selectively activates cardiac myosin by increasing the myosin ATPase rate. In isolated cardiac myocytes, Omecamtiv mecarbil results in increase of myocyte contractility and overcomes of the myosin inhibitor BDM without increasing the calcium transient or inhibiting the PDE pathway. [
In vivo
Omecamtiv mecarbil significantly increases fractional shortening starting at 0.4 mM plasma concentrations in SD rats, sham animals and in rats with heart failure. In conscious dogs with myocardial infarction (MI-sHF), Omecamtiv mecarbil leads to a significant increase in wall thickening (25%), stroke volume (44%), cardiac output (22%) and left ventricular (LV) systolic ejection time (26%). In addition, Omecamtiv mecarbil also results in the decreases of some hemodynamic parameters including heart rate, mean left atrial pressure, and LV end-diastolic pressure. In conscious dogs with left ventricular hypertrophy (LVH-sHF), Omecamtiv mecarbil leads to similar and not statistically different effects on hemodynamic parameters.
Biological Activity
omecamtiv mecarbil (ck-1827452) is the first potent cardiac myosin activator that can specifically activate the cardiac myosin s1 domain but not other muscle myosins. in
references
1. malik fi1, hartman jj, elias ka, morgan bp, rodriguez h, brejc k, anderson rl, sueoka sh, lee kh, finer jt, sakowicz r, baliga r, cox dr, garard m,godinez g, kawas r, kraynack e, lenzi d, lu pp, muci a, niu c, qian x, pierce dw, pokrovskii m, suehiro i, sylvester s, tochimoto t, valdez c, wang w,katori t, kass da, shen yt, vatner sf, morgans dj. cardiac myosin activation: a potential therapeutic approach for systolic heart failure. science. 2011 mar 18;331(6023):1439-43.
Check Digit Verification of cas no
The CAS Registry Mumber 873697-71-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,7,3,6,9 and 7 respectively; the second part has 2 digits, 7 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 873697-71:
(8*8)+(7*7)+(6*3)+(5*6)+(4*9)+(3*7)+(2*7)+(1*1)=233
233 % 10 = 3
So 873697-71-3 is a valid CAS Registry Number.
873697-71-3Relevant articles and documents
ALTERNATE PROCESSES FOR THE PREPARATION OF OMECAMTIV MECARBIL
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, (2021/04/17)
Aspects of the present application relate to process for the preparation of Omecamtiv mecarbil and salts thereof. Specific aspects relate to novel urea intermediate, preparative process thereof and its use in the preparation of Omecamtiv mecarbil and salts thereof. The improved process for the preparation of Omecamtiv mecarbil are industrially viable.
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.
Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions
Breitler, Simon,Oldenhuis, Nathan J.,Fors, Brett P.,Buchwald, Stephen L.
supporting information; experimental part, p. 3262 - 3265 (2011/08/07)
A facile synthesis of unsymmetrical N,N′-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation-deprotection protocol, followed by a second arylation.