title: Design and synthesis of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines as dipeptidyl peptidase IV inhibitors.
abstract: The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg(-1) . The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Linrong
authors.initials: L
authors.lastname: Zhu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Qiu
authors.forename: Mingbo
authors.initials: M
authors.lastname: Su
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Xia
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D003959:Diamines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D018819:Dipeptidyl Peptidase 4