Alpha myosin-inducing compounds and contractility

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is a diverse group of cardiovascular diseases that affects millions of Americans, with approximately 550,000 new cases diagnosed each year. The annual estimated health care cost is $10-40 billion, and it is predicted that the incidence of CHF will increase over the next decade. Patients diagnosed with CHF have a persistently poor prognosis, emphasizing the need for additional novel treatment approaches. The initial compensatory response in the disease process is thought to improve cardiac function, but the heart undergoes decompensation and cardiac function deteriorates if the hypertrophy is sustained. Eventually, CHF culminates in the clinical symptom of cardiac pump dysfunction. The relative abundance of isoforms of certain contractile proteins are altered during the disease process and contribute to the contractile defects. Myosin is the most abundant protein found in the contractile apparatus, and is responsible for mediating contraction through its interaction with actin. Two myosin isoforms are found in the heart (alpha and beta),and the relative proportion of these isoforms is dramatically affected in animal models of hypertrophy and in patients with end-stage CHF. Therefore, a novel approach to treat CHF patients is to restore myosin isoform expression to those resembling healthy individuals. Myogen, Inc. seeks to identify lead compounds that increase protein levels of a myosin heavy chain, a contractile protein that is severely downregulated in heart failure. These therapeutic agents can be used to improve cardiac contractile performance and induce reverse remodeling in CHF patients. In this Phase I proposal, some novel compounds recently discovered at Myogen will be tested to assess their effect on contractility in vitro. In a future Phase II proposal, additional compounds will be identified using a high throughput screening assay developed at Myogen, and compounds that improve contractility in vitro will be studied in rat models of cardiac hypertrophy. Phase III will focus on optimizing compounds through the use of medicinal chemistry until a lead compound is identified with the desired characteristics suitable for advancement to clinical studies.