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 analogues 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 analogues 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 analogues for treatment of heart failure has been expanded. |
申请人 |
UNIVERSITY OF CONNECTICUT;THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES;LIANG, BRUCE;JACOBSON, KENNETH A.;JOSHI, BHALCHANDRA V.;KUMAR, THATIKONDA SANTHOSH |
发明人 |
LIANG, BRUCE;JACOBSON, KENNETH A.;JOSHI, BHALCHANDRA V.;KUMAR, THATIKONDA SANTHOSH |