(N)-methanocarba Phosphonate Analogues of 5'-AMP as Cardioprotective Agents

This technology includes the use of the (N)-methanocarba phosphonate analogues of 5’-AMP as cardioprotective agents for use in conditions such as cardiomyopathy and heart failure. We previously found a compound, MRS2339 (a phosphate derivative that can be slowly cleaved in vivo and lose potency), which activates the appropriate receptors and is protective in models of heart failure in several species (mouse, dog). MRS2339 is a phosphate derivative that can be slowly cleaved in vivo and lose potency. We now extend this technology to more stable derivatives, i.e. phosphonates that are not subject to hydrolysis because they contain the stable C-P bond. Like MRS2339, they are held in the receptor-preferred conformation by virtue of the (N)-methanocarba ring system in place of the ribose moiety. Note that we previously applied the methanocarba ring system to nucleosides and nucleotides that are selective ligands of the adenosine and P2Y receptors, so some of the synthetic routes to the new compounds are common to both areas of study (i.e., previously GPCRs and now P2X ion channels).