Structure-Based Drug Design of Bisubstrate Inhibitors of Phenylethanolamine N‑Methyltransferase Possessing Low Nanomolar Affinity at Both Substrate Binding Domains1

The enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a2-adrenoceptor, which complicates the interpretation of their pharmacology. A bisubstrate analogue approach offers the potential for development of highly selective inhibitors of PNMT. This paper documents the design, synthesis, and evaluation of such analogues, several of which were found to possess human PNMT (hPNMT) inhibitory potency 19 and 29) were co-crystallized with hPNMT and the resulting structures revealed both compounds bound as predicted, simultaneously occupying both substrate binding domains. This bisubstrate inhibitor approach has resulted in one of the most potent (20) and selective (vs the a2‑adrenoceptor) inhibitors of hPNMT yet reported.