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

[Display omitted] 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 antagoni...

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Published in:Bioorganic & medicinal chemistry 2016-06, Vol.24 (11), p.2486-2503
Main Authors: Igawa, Hideyuki, Takahashi, Masashi, Shirasaki, Mikio, Kakegawa, Keiko, Kina, Asato, Ikoma, Minoru, Aida, Jumpei, Yasuma, Tsuneo, Okuda, Shoki, Kawata, Yayoi, Noguchi, Toshihiro, Yamamoto, Syunsuke, Fujioka, Yasushi, Kundu, Mrinalkanti, Khamrai, Uttam, Nakayama, Masaharu, Nagisa, Yasutaka, Kasai, Shizuo, Maekawa, Tsuyoshi
Format: Article
Language:English
Subjects:
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - chemistry
Anti-Obesity Agents - pharmacology
Antiobesity agent
Benzimidazole
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Bioactivation
CYP3A4 time-dependent inhibition
Cytochrome P-450 CYP3A - metabolism
Dose-Response Relationship, Drug
Drug Design
Humans
Male
MCH
MCHR1 antagonist
Molecular Structure
Obesity - drug therapy
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Rats
Rats, Inbred F344
Receptors, Somatostatin - antagonists & inhibitors
Structure-Activity Relationship
Thiophene
Time Factors
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.04.011