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-alkylated compound 5 and (2) reducing 5 with NaBH4. Selective inhibition of AMPDA was realized when the N3-substituent contained a carboxylic acid moiety. For example, compound 7b which has a hexanoic acid side chain inhibited AMPDA with a K-i = 4.2 mu M and ADA with a K-i = 280 mu M. Substitution of large lipophilic groups a to the carboxylate provided a moderate potency increase with maintained selectivity as exemplified by the cl-benzyl analogue 7j (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 suitable for testing whether selective inhibition of AMPDA can protect tissue from ischemic damage by increasing local adenosine concentrations at the site of injury and/or by minimizing adenylate loss.