Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1receptor antagonist.
Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1receptor. Orally administered compound 24d (6-24μmol/kg) showed ex vivo CRF1receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1receptor antagonists and the pharmacological profiles of compound 24d.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: michiyo.mochizuki@takeda.com.
Michiyo
M
Mochizuki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takuto
T
Kojima
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Katsumi
K
Kobayashi
CMC Center, Takeda Pharmaceutical Company Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Etsuo
E
Kotani
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Yuji
Y
Ishichi
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Naoyuki
N
Kanzaki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hideyuki
H
Nakagawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Teruaki
T
Okuda
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Yohei
Y
Kosugi
Taisho Pharmaceutical Company Ltd., 403, Yoshino-cho 1-chome, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
Takahiko
T
Yano
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Yuu
Y
Sako
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Maiko
M
Tanaka
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Kazuyoshi
K
Aso
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012756:Sheep; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
C000621706:4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole; D001562:Benzimidazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
7-Alkylbenzimidazole; CRF(1) receptor antagonist; Corticotropin-releasing factor; Metabolic stability