AMP DERIVATIVES FOR TREATING CARDIAC DISEASES

摘要

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.