Discovery of 1, 2, 3, 4-tetrahydropyrimido[1, 2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Kojima, Takuto; Mochizuki, Michiyo; Takai, Takafumi; Hoashi, Yasutaka; Morimoto, Sachie; Seto, Masaki; Nakamura, Minoru; Kobayashi, Katsumi; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Kosugi, Yohei; Yano, Takahiko; Aso, Kazuyoshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 9(2018)
• Page Start: 2229
• Page End: 2250
• Publication Date: 2018-05-15
• Subjects: CRF1 receptor antagonists -- 1, 2, 3, 4-Tetrahydropyrimido[1, 2-a]benzimidazole -- Tricyclic ring system -- Stress-related disorders; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.01.020
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A new class of corticotropin releasing factor 1 (CRF1 ) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives2a –e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives2a –e showed CRF1 receptor binding activity with IC50 values of less than 400 nM, and the 1, 2, 3, 4-tetrahydropyrimido-[1, 2- a ]benzimidazole derivative2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50 = 7.1 nM). To optimize the pharmacokinetic profiles of lead compound2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound42c -R, which exhibited potent CRF1 receptor binding activity (IC50 = 58 nM) with good oral bioavailability (F = 68% in rats). Compound42c -R exhibited dose-dependent inhibition of [ 125 I]-CRF binding in the frontal cortex (5 and 10 mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10 mg/kg, p.o.). These results suggest that compound42c -R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies.