1447910-79-3

Upstream product

• 459-56-3 4-fluorobenzylic alcohol 
• 586373-37-7 4-[(4-fluorobenzyl)oxy]pyridine 1-oxide 
• 1121-76-2 4-chloropyridine N-oxide 
• 337915-79-4 4-bromo-N²-methylbenzene-1,2-diamine 
• 321-23-3 4-bromo-2-fluoronitrobenzene 
• 302800-13-1 5-bromo-N-methyl-2-nitroaniline 
• 586373-38-8 4-[(4-fluorobenzyl)oxy]pyridine-2(1H)-one 
• 1447910-80-6 6-bromo-2-cyclopropyl-1-methyl-1H-benzo[d]imidazole 

Relevant academic research and scientific papers

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.

BENZIMIDAZOLE DERIVATIVES AS MCH RECEPTOR ANTAGONISTS

The present invention provides an aromatic ring compound having a melanin-concentrating hormone receptor antagonistic action and useful as an agent for the prophylaxis or treatment of obesity and the like. The present invention relates to a compound represented by the formula (I) wherein each symbol as defined in the specification, or a salt thereof.