Cytokinetics Announces Preclinical Data for CK-3773274 Presented at the American Chemical Society Spring 2021 Virtual Meeting
Next-In-Class Cardiac Myosin Inhibitor Optimized for Shallow Exposure Response and Pharmacokinetics to Enable Flexible Dose Titration
SOUTH SAN FRANCISCO, Calif., April 12, 2021 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that data related to the optimization of CK-3773274 (CK-274), including the
first disclosure of its chemical structure, were presented at the American Chemical Society Spring 2021 Virtual Meeting. The presentation reviewed scientific activities that involved evaluating
CK-274 and precursor compounds for their exposure-response relationship, projected human half-life, and potential for meaningful cytochrome P450 (CYP450) interactions. CK-274 is a next-in-class
cardiac myosin inhibitor discovered by company scientists, in development for the potential treatment of hypertrophic cardiomyopathy (HCM).
“These preclinical data provide a first look at the structure of our next-in-class cardiac myosin inhibitor, CK-274, and its performance in certain preclinical assays,” said Brad Morgan, Ph.D., Cytokinetics’ Senior Vice President, Research and Non-Clinical Development. “CK-274 was synthesized from a newly discovered and distinct chemical series following an optimization program that was intentionally focused on key compound physiochemical characteristics, such as a shallow dose-response relationship and a half-life that may enable flexible and timely dosing adjustments. We look forward to results from REDWOOD-HCM, the Phase 2 clinical trial of CK-274, which is designed to elaborate on how these differentiated properties may translate into its potential use in patients with obstructive HCM.”
Data presented described the primary optimization objectives, identification of an initial hit compound, and its subsequent chemical optimization, including preclinical characterization in biochemical assays, cardiac myocytes, and in vivo models of cardiac function. In cardiac myofibrils, the biochemical potency of CK-274 was 1.26 µM and it reduced cardiac myocyte contractility to 33% of baseline at 5 µM. Echocardiographic data from healthy rats showed that CK-274 reduced fractional shortening, a measure of cardiac function, in a dose- and exposure-dependent fashion. The pharmacodynamic window, characterized by the ratio of plasma concentrations required to achieve a 50% (IC50) and 10% (IC10) reduction in fractional shortening (IC50/IC10) was 9.6 for CK-274. The exposure-response relationship for CK-274 in healthy dogs was similar to that observed in rats.
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