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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.

Author information

1
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. bookser@mbasis.com

Abstract

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.

PMID:
10780908
DOI:
10.1021/jm9905413
[Indexed for MEDLINE]

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