AMP Deaminase Inhibitors. 4. Further N3-Substituted Coformycin Aglycon Analogues:  N3-Alkylmalonates as Ribose 5‘-Monophosphate Mimetics

AMP deaminase (AMPDA) inhibitors increase the levels of extracellular adenosine and preserve intracellular adenylate pools in cellular models of ATP depletion and therefore represent a potential new class of antiischemic drugs. Recently we reported that replacement of the ribose 5‘-monophosphate component of the very potent transition-state analogue AMPDA inhibitor coformycin monophosphate (1) with a simple alkylcarboxy group resulted in potent, selective, and cell-penetrating AMPDA inhibitors. Here we report that replacement of this alkylcarboxy group with an α-substituted alkylmalonic acid resulted in enhanced inhibitor potency. The lead compound, 3-(5,5-dicarboxy-6-(3-(trifluoromethyl)phenyl)-n-hexyl)coformycin aglycon (21), exhibited an AMPDA K i of 0.029 μM which is (3 × 105)-fold lower than the K M for the natural substrate AMP. A comparison of inhibitory potencies shows that the diacid analogues with α-benzyl substituents are 2−10-fold more inhibitory than similar monoacid−monoester, monoester−monoamide, or diester derivatives. Finally, these diacid analogues are 2−40-fold more potent inhibitors than the corresponding monocarboxylates.