AMP Deaminase Inhibitors. 5. Design, Synthesis, and SAR of a Highly Potent Inhibitor Series

A highly potent AMP deaminase (AMPDA) inhibitor series was discovered by replacing the N3 substitutents of the two lead AMPDA inhibitor series with a conformationally restricted group. The most potent compound, 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (24b), represents a 10- to 250-fold enhancement in AMPDA inhibitory potency without loss in the enzyme specificity. The potency of the inhibitor 24b (AMPDA K i = 0.002 μM) is 105-fold lower than the K m for the substrate AMP. It represents the most potent nonnucleotide AMPDA inhibitor known.