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

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• 作者：Hideyuki Igawa^a ; ^{hideyuki.igawa@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Masashi Takahashi^a ; Mikio Shirasaki^a ; Keiko Kakegawa^a ; Asato Kina^a ; Minoru Ikoma^a ; Jumpei Aida^a ; Tsuneo Yasuma^b ; Shoki Okuda^a ; Yayoi Kawata^a ; Toshihiro Noguchi^a ; Syunsuke Yamamoto^a ; Yasushi Fujioka^a ; Mrinalkanti Kundu^c ; Uttam Khamrai^c ; Masaharu Nakayama^a ; Yasutaka Nagisa^d ; Shizuo Kasai^a ; Tsuyoshi Maekawa^a
• 关键词：MCH ; melanin-concentrating hormone ; MCHR1 ; melanin-concentrating hormone receptor 1 ; CYP3A4 ; cytochrome P450 3A4 ; TDI ; time-dependent inhibition ; DIO ; diet-induced obesity ; hERG ; human ether-a-go-go related gene ; DMEDA ; N ; N&prime ; -dimethylethylenediamine ; HATU ; (1-[bis(dimethylamino)methylene]-1H-1 ; 2 ; 3-triazolo[4 ; 5-b]pyridinium 3-oxid hexafluorophosphate) ; DIPEA ; N ; N-diisopropylethylamine ; TFAA ; trifluoroacetic anhydride ; ADDP ; 1 ; 1&prime ; -(azodicarbonyl)dipiperidine ; MW ; microwave ; CHO ; Chinese
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：24
• 期：11
• 页码：2486-2503
• 全文大小：3166 K

文摘

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.