Compositions and methods to treat cardiac diseases

US8822434B2 · kind B2 · utility

Assignees

• UNIVERSITY OF CONNECTICUT · US
• The United States of America, as represented by the Secretary, Department of Health and Human Services · US

Inventors

• Bruce Liang · Avon, US
• Kenneth A. Jacobson · Silver Spring, US
• Bhalchandra V. Joshi · Madison, US
• Thatikonda Santhosh Kumar · Gaithersburg, US

Key dates

• Filing date: Feb 22, 2011
• Grant date: Sep 2, 2014
• Expiry date: Jul 10, 2032

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07F9/65616
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.