AMP deaminase (AMPDA) inhibitors increase the levels of extracellular adeno
sine and preserve intracellular adenylate pools in cellular models of ATP d
epletion and therefore represent a potential new class of antiischemic drug
s. Recently we reported that replacement of the ribose 5'-monophosphate com
ponent of the very potent transition-state analogue AMPDA inhibitor coformy
cin monophosphate (1) with a simple alkylcarboxy group resulted in potent,
selective, and cell-penetrating AMPDA inhibitors. Here we report that repla
cement of this alkylcarboxy group with an a-substituted alkylmalonic acid r
esulted in enhanced inhibitor potency. The lead compound, 3-(5,5-dicarboxy-
6-(3-(trifluoromethyl)phenyl)-n-hexyl)coformation aglycon (21), exhibited a
n AMPDA K-i of 0.029 mu M which is (3 x 10(5))-fold lower than the K-M for
the natural substrate AMP. A comparison of inhibitory potencies shows that
the diacid analogues with cr-benzyl substituents are 2-10-fold more inhibit
ory than similar monoacid-monoester monoester-monoamide, or diester derivat
ives. Finally, these diacid analogues are 2-40-fold more potent inhibitors
than the corresponding monocarboxylates.