title: Current basis for discovery and development of aryl hydrocarbon receptor antagonists for experimental and therapeutic use in atherosclerosis.
abstract: The important role played by aryl hydrocarbon receptor activation in the pathophysiology of atherosclerosis induced by cigarette smoke exposure has spurred the clinical interest in the development of aryl hydrocarbon receptor antagonists with atheroprotective efficacy. A few aryl hydrocarbon receptor antagonists were developed but the lack of structural information regarding the receptor ligand binding domain resulted in several limitations in the pharmacological properties of these compounds including partial agonism, allosterism, non-selectivity, cytotoxicity and susceptibility to bioactivation. These limitations make the progress of preclinical and clinical assays with the available aryl hydrocarbon receptor antagonists difficult. There is a great interest in developing pure, competitive, selective, nontoxic and resistant to bioactivation aryl hydrocarbon receptor antagonists. Current technology permits the development of pharmacologically ideal antagonists based on the chemical features of the aryl hydrocarbon receptor ligand binding domain. According to these characteristics, chlorinated derivatives of trans-stilbene meta-substituted with electrophilic aromatic directing groups would be effective prototypes for pure, competitive, selective, nontoxic and resistant to bioactivation antagonists for such receptor.
authors.affiliation: Computational Laboratory of Pharmaceutical Chemistry, Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP), Universidade de São Paulo (USP), Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address: l.pernomian@usp.br.
authors.forename: Larissa
authors.initials: L
authors.lastname: Pernomian
authors.affiliation: Computational Laboratory of Pharmaceutical Chemistry, Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP), Universidade de São Paulo (USP), Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Carlos H T P
authors.initials: CHTP
authors.lastname: da Silva
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D018336:Receptors, Aryl Hydrocarbon
keywords: Aryl hydrocarbon receptor antagonists; Atherosclerosis; Cigarette smoke; Drug design; Molecular modeling