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

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journal contribution
posted on 17.01.2001, 00:00 by Srinivas Rao Kasibhatla, Brett C. Bookser, Wei Xiao, Mark D. Erion
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 Ki = 0.002 μM) is 105-fold lower than the Km for the substrate AMP. It represents the most potent nonnucleotide AMPDA inhibitor known.