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. Issue 11 (1st June 2016)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 11(2016)
• Page Start: 2486
• Page End: 2503
• Publication Date: 2016-06-01
• Subjects: 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′-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′-(azodicarbonyl)dipiperidine -- MW microwave -- CHO Chinese Hamster Ovary -- TM transmembrane -- GSH glutathione -- HLM human liver microsomes; MCHR1 antagonist -- MCH -- Antiobesity agent -- Benzimidazole -- Thiophene -- Bioactivation -- CYP3A4 time-dependent inhibition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.011
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compound6a bearing a 1 H -benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative1 . Optimization of6a 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-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.