AMP deaminase inhibitors. 2. Initial discovery of a non-nucleotide transition-state inhibitor series

A series of N3-substituted coformycin aglycon analogues are described that inhibit adenosine 5'-monophosphate deaminase (AMPDA) or adenosine deaminase (ADA). The key steps involved in the preparation of these compounds are (1 ) treating the sodium salt of 6,7-dihydroimidazo-[4,5-d][1,3]diazepin-8(3H) -one (4) with an alkyl bromide or an alkyl mesylate to generate the N3-alky lated compound 5 and (2) reducing 5 with NaBH4. Selective inhibition of AMP DA was realized when the N3-substituent contained a carboxylic acid moiety. For example, compound 7b which has a hexanoic acid side chain inhibited AM PDA with a K-i = 4.2 mu M and ADA with a K-i = 280 mu M. Substitution of la rge lipophilic groups a to the carboxylate provided a moderate potency incr ease with maintained selectivity as exemplified by the cl-benzyl analogue 7 j (AMPDA K-i = 0.41 mu M and ADA K-i > 1000 mu M). These compounds, as well as others described in this series of papers, are the first compounds suit able for testing whether selective inhibition of AMPDA can protect tissue f rom ischemic damage by increasing local adenosine concentrations at the sit e of injury and/or by minimizing adenylate loss.