title: 1-((3S,4S)-4-amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes.
abstract: A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Andrews
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: John W
authors.initials: JW
authors.lastname: Benbow
authors.forename: David A
authors.initials: DA
authors.lastname: Boyer
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Yu
authors.initials: Y
authors.lastname: Hui
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: R Kirk
authors.initials: RK
authors.lastname: McPherson
authors.forename: Constantin
authors.initials: C
authors.lastname: Neagu
authors.forename: Janice C
authors.initials: JC
authors.lastname: Parker
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schneider
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Maria A
authors.initials: MA
authors.lastname: VanVolkenberg
authors.forename: William J
authors.initials: WJ
authors.lastname: Zembrowski
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines