title: Synthesis, SAR study, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase (FAAH) inhibitors.
abstract: A series of piperazine ureas was designed, synthesized, and evaluated for their potential as novel orally available fatty acid amide hydrolase (FAAH) inhibitors that are therapeutically effective against pain. We carried out an optimization study of the lead compound 3 to improve its DMPK profile as well as in vitro potency. We identified the thiazole compound 60j with potent inhibitory activity, high brain permeability, and good bioavailability. Compound 60j showed a potent and dose-dependent anti-nociceptive effect in the acetic acid-induced writhing test in mice.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. mitsunori.kouno@takeda.com
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kono
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Toru
authors.initials: T
authors.lastname: Kawamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishimura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kiyota
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.forename: Junichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Igaki
authors.forename: Craig A
authors.initials: CA
authors.lastname: Behnke
authors.forename: Masato
authors.initials: M
authors.lastname: Shimojo
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010146:Pain / Q000188:drug therapy / Q000201:enzymology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000077489:Piperazine; D010879:Piperazines; D013844:Thiazoles; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases