1. 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
- Author
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Uttam Khamrai, Jumpei Aida, Mrinalkanti Kundu, Tsuneo Yasuma, Mikio Shirasaki, Shoki Okuda, Shizuo Kasai, Syunsuke Yamamoto, Asato Kina, Masashi Takahashi, Toshihiro Noguchi, Yasutaka Nagisa, Yayoi Kawata, Hideyuki Igawa, Minoru Ikoma, Yasushi Fujioka, Keiko Kakegawa, Tsuyoshi Maekawa, and Masaharu Nakayama
- Subjects
Male ,0301 basic medicine ,Imidazopyridine ,Benzimidazole ,Time Factors ,Pyridones ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Thiophene ,Animals ,Cytochrome P-450 CYP3A ,Humans ,HATU ,Obesity ,Receptors, Somatostatin ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,Organic Chemistry ,Sulfoxide ,Rats, Inbred F344 ,Rats ,Melanin-concentrating hormone receptor ,030104 developmental biology ,chemistry ,Drug Design ,Molecular Medicine ,Benzimidazoles ,Anti-Obesity Agents ,Lead compound ,030217 neurology & neurosurgery - Abstract
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(1 H )-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(1 H )-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1 H -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 CF 3 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-1 H -benzimidazol-6-yl)pyridin-2(1 H )-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.
- Published
- 2016