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J Med Chem. 2000 Apr 20;43(8):1519-24.

AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics.

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Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA.


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 alpha-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 microM 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 alpha-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.

[Indexed for MEDLINE]

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