title: Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists.
abstract: A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50=27nM, 56nM, respectively). This compound exhibited ex vivo (125)I-Tyr(0) ((125)I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure-activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: michiyo.mochizuki@takeda.com.
authors: Michiyo
authors: M
authors: Mochizuki
authors: CMC Center, Takeda Pharmaceutical Company Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Masakuni
authors: M
authors: Kori
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Mitsunori
authors: M
authors: Kono
authors: Taisho Pharmaceutical Company Ltd, 403, Yoshino-cho 1-chome, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors: Takahiko
authors: T
authors: Yano
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yuu
authors: Y
authors: Sako
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Maiko
authors: M
authors: Tanaka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Naoyuki
authors: N
authors: Kanzaki
authors: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors: Albert C
authors: AC
authors: Gyorkos
authors: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors: Christopher P
authors: CP
authors: Corrette
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Kazuyoshi
authors: K
authors: Aso
mesh_terms: D000586:Amination; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D001562:Benzimidazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; C031000:benzimidazole
keywords: 7-Arylaminobenzimidazole; CRF(1) receptor antagonist; Corticotropin-releasing factor