title: Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.
abstract: The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Corbett
authors.forename: K
authors.initials: K
authors.lastname: Dirico
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.forename: B P
authors.initials: BP
authors.lastname: Boscoe
authors.forename: S D
authors.initials: SD
authors.lastname: Doran
authors.forename: D
authors.initials: D
authors.lastname: Boyer
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: M
authors.initials: M
authors.lastname: Ammirati
authors.forename: M A
authors.initials: MA
authors.lastname: Vanvolkenburg
authors.forename: R K
authors.initials: RK
authors.lastname: McPherson
authors.forename: J C
authors.initials: JC
authors.lastname: Parker
authors.forename: E D
authors.initials: ED
authors.lastname: Cox
mesh_terms: D000586:Amination; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D003486:Cyanides / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003486:Cyanides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011758:Pyrroles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D001554:Benzene