title: Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV.
abstract: The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.
authors.affiliation: Takeda San Diego, Inc., 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wallace
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Stafford
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Skene
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.forename: Bumsup
authors.initials: B
authors.lastname: Lee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Andy
authors.initials: A
authors.lastname: Jennings
authors.forename: Rongda
authors.initials: R
authors.lastname: Xu
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kassel
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Kaldor
authors.forename: Marc
authors.initials: M
authors.lastname: Navre
authors.forename: David R
authors.initials: DR
authors.lastname: Webb
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gwaltney
mesh_terms: D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D008252:Macaca fascicularis; D008958:Models, Molecular; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011744:Pyrimidinones