Acetamidine Lysine Derivative, N-(5(S)-amino-6,7-dihydroxyheptyl)ethanimidamide Dihydrochloride:  A Highly Selective Inhibitor of Human Inducible Nitric Oxide Synthase

Journal of Medicinal Chemistry
1998.0

Abstract

Selective inhibitors of inducible nitric oxide synthase (iNOS) have therapeutic potential for diseases mediated by overproduction of nitric oxide (NO). Previously reported arginine-based NOS inhibitors lack iNOS selectivity, while N-(Iminoethyl)-L-lysine (NIL) is a selective iNOS inhibitor with 30-fold selectivity over endothelial NOS (eNOS). We replaced the carboxyl group of NIL with a vicinal glycol to yield N-(5(S)-amino-6,7-dihydroxyheptyl)ethanimidamide dihydrochloride (2). Compound 2 inhibits iNOS with an IC50 of 12 µM (slightly less potent than NIL) but shows a striking ~700-fold selectivity for iNOS over eNOS and 12-fold selectivity over neuronal NOS (nNOS). Chirality is critical for activity, as 2 is ~4 times more potent than its diastereomer 11. We have identified 2 as a highly selective iNOS inhibitor and shown that the vicinal diol moiety is an effective isostere for the carboxyl group of NIL.

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