Bioorganic and Medicinal Chemistry p. 1556 - 1570 (2017)
Update date:2022-08-04
Topics:
Mochizuki, Michiyo
Kojima, Takuto
Kobayashi, Katsumi
Kotani, Etsuo
Ishichi, Yuji
Kanzaki, Naoyuki
Nakagawa, Hideyuki
Okuda, Teruaki
Kosugi, Yohei
Yano, Takahiko
Sako, Yuu
Tanaka, Maiko
Aso, Kazuyoshi
Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50= 9.5 nM) and in vitro antagonistic activity (IC50= 88 nM) but is rapidly metabolized by human hepatic microsomes (182 μL/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 (87 μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50= 4.1 nM), in vitro antagonistic activity (IC50= 44 nM), and slow dissociation from the CRF1receptor. Orally administered compound 24d (6–24 μmol/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.
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Doi:10.1007/BF00955843
(1987)Doi:10.1016/0223-5234(92)90004-K
(1992)Doi:10.1021/jm100505n
(2010)Doi:10.1021/jo01360a017
(1957)Doi:10.1021/ja01212a011
(1946)Doi:10.1002/jccs.200800196
(2008)