title: Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.
abstract: Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Ji
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Xia
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; East China of Normal University, 3663 Zhongshan Road, Shanghai 200062, People's Republic of China.
authors.forename: Mingbo
authors.initials: M
authors.lastname: Su
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Dong
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wan
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Electronic address: jli@mail.shcnc.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China. Electronic address: hljiang@mail.shcnc.ac.cn.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Electronic address: hliu@mail.shcnc.ac.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D018819:Dipeptidyl Peptidase 4
keywords: DPP4 inhibitors; GLP-1; Oral bioavailability; Oral glucose tolerance tests; Selectivity; hERG