1022249-27-9

Upstream product

• 53553-14-3 2-chloro-3-nitrobenzoic acid methyl ester 
• 913297-15-1 methyl 2-(methylamino)-3-nitrobenzoate 
• 851889-13-9 methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate 
• 913298-61-0 2,4-dichloro-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole 
• 1022249-15-5 2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole 
• 913297-16-2 methyl 3-amino-2-(methylamino)benzoate 
• 1022251-49-5 3-chloro-4-{[4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-yl]oxy}-5-methylbenzoic acid 

Relevant academic research and scientific papers

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= 9.5 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.

BENZIMIDAZOLE COMPOUNDS

There is provided a compound of the formula (1) wherein R1 is an optionally substituted C1-10 alkyl; R2 is H, or a C1-6 alkyl which may be substituted with 1 to 3 substituents; R3 is a 5- or 6-membered aromatic group which may be substituted with 1 to 5 substituents, wherein the 5- or 6-membered aromatic group may be fused with a 5- or 6- membered ring which may be substituted with 1 to 3 C1-6 alkyls; R4 is a hydrogen, a halogen, a hydroxy, a cyano, a C1-6 alkyl or a C1-6 alkoxy; Z is -O-, -S-, -SO-, -SO2-, or - NR5- wherein R5 is a hydrogen or a C1-6 alkyl; or a salt thereof or a prodrug thereof, which have CRF receptor antagonist activity and use thereof.