Effect of the Selective Cardiac Myosin Activator, Omecamtiv Mecarbil, on Left Atrial Performance in Healthy Men

Habibzadeh, M. Reza; Schiller, Nelson B.; Malik, Fady I.; Chen, Michael M.; Saikali, Khalil G.; Wolff, Andrew; Goldman, Jonathan H.; Teerlink, John R.

doi:10.1016/j.cardfail.2010.06.249

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“…Recently, drugs have been developed that directly target myosin. A direct activator of cardiac myosin has demonstrated promise for the treatment of heart failure (Shen et al, 2010;Malik et al, 2011) and is currently in clinical trials (Cytokinetics, 2007-2009, Greenberg et al, 2009Habibzadeh et al, 2010).…”

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confidence: 99%

Inhibition of Smooth Muscle Myosin as a Novel Therapeutic Target for Hypertension

Zhao¹,

Ho²,

Abarzúa³

et al. 2011

J Pharmacol Exp Ther

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We examined a novel therapeutic approach for hypertension, a small-molecule direct inhibitor of smooth muscle myosin, CK-2018448 (CK-448), which is an N,N'-alkylurea (U.S. Patent Publication 2009 -0275537 A1) in conscious dogs with renal hypertension and compared its efficacy with that of a calcium channel blocker, amlodipine. Dogs were instrumented with a miniature left ventricular pressure gauge, an aortic pressure catheter, and ultrasonic flow probes in the ascending aorta and renal and iliac arteries for measurement of cardiac output and regional blood flow. In the hypertensive state, mean arterial pressure increased from 101 Ϯ 3.8 to 142 Ϯ 1.9 mm Hg. At the doses selected, CK-448 and amlodipine increased cardiac output similarly (30 Ϯ 11% versus 33 Ϯ 6.4%) and similarly reduced mean arterial pressure (Ϫ22 Ϯ 3.6% versus Ϫ16 Ϯ 3.4%) and total peripheral resistance (Ϫ36 Ϯ 5.9% versus Ϫ37 Ϯ 5.8%). CK-448 had the greatest vasodilator effect in the renal bed, where renal blood flow increased by 46 Ϯ 9.0%, versus 11 Ϯ 3.4% for amlodipine (p Ͻ 0.01). CK-488 produced significantly less vasodilation in the limb, where iliac blood flow did not change; in contrast, it rose by 48 Ϯ 12% with amlodipine (p Ͻ 0.01). The minimal effects on limb blood flow could limit the development of peripheral edema, an adverse side effect of Ca 2ϩ channel blockers. In addition, in a rodent model of hypertension, oral administration of a smooth muscle myosin inhibitor resulted in a sustained antihypertensive effect. Thus, the smooth muscle myosin inhibitor's preferential effect on renal blood flow makes this drug mechanism particularly appealing, because many patients with hypertension have renal insufficiency, and patients with heart failure could benefit from afterload reduction coupled with enhanced renal blood flow.

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