The Discovery and Development of the N-Substituted trans-3,4-Dimethyl-4-(3′-hydroxyphenyl)piperidine Class of Pure Opioid Receptor Antagonists

• Published in: ChemMedChem Vol. 9; no. 8; pp. 1638 - 1654
• Main Authors: Carroll, F. Ivy, Dolle, Roland E.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.08.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: alvimopan; Crystallography, X-Ray; drug design; Drug Evaluation, Preclinical; Humans; JDTic; medicinal chemistry; Narcotic Antagonists - chemistry; Narcotic Antagonists - metabolism; opioid antagonists; Piperidines - chemistry; Piperidines - metabolism; Protein Binding; Protein Structure, Tertiary; Receptors, Opioid - chemistry; Receptors, Opioid - metabolism; Structure-Activity Relationship; alvimopan; drug design; opioid antagonists; JDTic; medicinal chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402142

N‐Substituted trans‐3,4‐dimethyl‐4‐(3‐hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1) early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2) the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3) the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X‐ray structure of the human κ opioid receptor is discussed. Pure antagonism: This review outlines the discovery of the novel N‐substituted 3,4‐dimethyl‐4‐(3‐hydroxyphenyl)piperidine opioid receptor antagonist pharmacophore and its use in the discovery of the peripherally selective μ opioid receptor (MOR) antagonist alvimopan and the selective κ opioid receptor (KOR) antagonist JDTic, which was used to obtain the X‐ray structure of the human KOR.