title: Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.
abstract: Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687 nM. Among them, 72 has an IC50 value of 11.7 nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9 nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Chai
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States. Electronic address: Taosheng.Chen@stjude.org.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000090702:Constitutive Androstane Receptor; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006801:Humans; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; C000611514:ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo(b,f)azepin-3-yl)carbamate
keywords: CINPA1; Constitutive androstane receptor; Inverse agonist; TR-FRET