Piperidinyl-2-phenethylamino inhibitors of DPP-IV for the treatment of type 2 diabetes.
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.
Benbow
John W
JW
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, United States. orgodoc@comcast.net
Andrews
Kim A
KA
Aubrecht
Jiri
J
Beebe
David
D
Boyer
David
D
Doran
Shawn
S
Homiski
Michael
M
Hui
Yu
Y
McPherson
Kirk
K
Parker
Janice C
JC
Treadway
Judith
J
Vanvolkenberg
Maria
M
Zembrowski
William J
WJ
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D010880:Piperidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4