title: Piperidinyl-2-phenethylamino inhibitors of DPP-IV for the treatment of type 2 diabetes.
abstract: A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the 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, United States. orgodoc@comcast.net
authors.forename: John W
authors.initials: JW
authors.lastname: Benbow
authors.forename: Kim A
authors.initials: KA
authors.lastname: Andrews
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: David
authors.initials: D
authors.lastname: Beebe
authors.forename: David
authors.initials: D
authors.lastname: Boyer
authors.forename: Shawn
authors.initials: S
authors.lastname: Doran
authors.forename: Michael
authors.initials: M
authors.lastname: Homiski
authors.forename: Yu
authors.initials: Y
authors.lastname: Hui
authors.forename: Kirk
authors.initials: K
authors.lastname: McPherson
authors.forename: Janice C
authors.initials: JC
authors.lastname: Parker
authors.forename: Judith
authors.initials: J
authors.lastname: Treadway
authors.forename: Maria
authors.initials: M
authors.lastname: Vanvolkenberg
authors.forename: William J
authors.initials: WJ
authors.lastname: Zembrowski
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D010880:Piperidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4