title: Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation.
abstract: Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
authors.affiliation: Asubio Pharma Co., Ltd.
authors.forename: Bitoku
authors.initials: B
authors.lastname: Takahashi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Funami
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.forename: Satomi
authors.initials: S
authors.lastname: Kanki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Muto
mesh_terms: D015120:6-Aminonicotinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D054440:Receptors, Ghrelin; D015120:6-Aminonicotinamide; D051544:Cytochrome P-450 CYP3A