Therapeutic Potential of Small Molecules Acting Directly on The Contractile Apparatus of Cardiac Muscle

Abstract

Abstract Background: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulting in unwanted effects. In contrast, targeting the sarcomere directly, aided by high throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Method: Here in, an extensive literature review of 27 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in 8 different criteria. Findings: Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out showing a potential therapeutic value in HCM, DCM or HF. Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+ sensitiser) all are small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil is currently under phase III trials for heart failure, while results from phase III EXPLORER-HCM trial were recently published indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as ‘Recouplers’ was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. Conclusion: The contractile apparatus is a promising target for new drug development.