title: Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors.
abstract: Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400, USA. guohua.zhao@bms.com
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Prakash C
authors.initials: PC
authors.lastname: Taunk
authors.forename: David R
authors.initials: DR
authors.lastname: Magnin
authors.forename: Ligaya M
authors.initials: LM
authors.lastname: Simpkins
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Aiying
authors.initials: A
authors.lastname: Wang
authors.forename: James G
authors.initials: JG
authors.lastname: Robertson
authors.forename: Jovita
authors.initials: J
authors.lastname: Marcinkeviciene
authors.forename: Doree F
authors.initials: DF
authors.lastname: Sitkoff
authors.forename: Rex A
authors.initials: RA
authors.lastname: Parker
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kirby
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D001665:Binding Sites; D003500:Cyclization; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary
chemical_list: D009570:Nitriles; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4