Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor

…, EK Bayburt, MP Capparelli, RS Bohacek…

Index: MacPherson; Bayburt; Capparelli; Bohacek; Clarke; Ghai; Sakane; Berry; Peppard; Trapani Journal of Medicinal Chemistry, 1993 , vol. 36, # 24 p. 3821 - 3828

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Citation Number: 32

Abstract

A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50= 3 nM). In ...