title: (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor.
abstract: A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
authors.affiliation: Pfizer Global Research & Development, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ammirati
authors.forename: Kim M
authors.initials: KM
authors.lastname: Andrews
authors.forename: David D
authors.initials: DD
authors.lastname: Boyer
authors.forename: Anne M
authors.initials: AM
authors.lastname: Brodeur
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Bernard
authors.initials: B
authors.lastname: Hulin
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: R Kirk
authors.initials: RK
authors.lastname: McPherson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Orena
authors.forename: Janice C
authors.initials: JC
authors.lastname: Parker
authors.forename: Jana
authors.initials: J
authors.lastname: Polivkova
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Soglia
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Maria A
authors.initials: MA
authors.lastname: VanVolkenburg
authors.forename: Donald C
authors.initials: DC
authors.lastname: Wilder
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C541282:(3,3-difluoropyrrolidin-1-yl)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl)methanone; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D011759:Pyrrolidines