AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon analogues.

N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA) inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1, 3]diazepin-8-ol (2) described in the previous article with various carboxyarylalkyl groups resulted in compounds with 10-100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy-5-ethylphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4, 5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a K(i) = 0. 06 microM. The compounds within the series also exhibited >1000-fold specificity for AMPDA relative to adenosine deaminase.