title: Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.
abstract: Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Mochizuki
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yano
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Sako
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Gyorkos
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Corrette
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Pratt
authors.affiliation: Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Aso
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010913:Pituitary-Adrenal System / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: D001562:Benzimidazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone