(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.
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.
Ammirati
Mark J
MJ
Pfizer Global Research & Development, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340, United States.
Andrews
Kim M
KM
Boyer
David D
DD
Brodeur
Anne M
AM
Danley
Dennis E
DE
Doran
Shawn D
SD
Hulin
Bernard
B
Liu
Shenping
S
McPherson
R Kirk
RK
Orena
Stephen J
SJ
Parker
Janice C
JC
Polivkova
Jana
J
Qiu
Xiayang
X
Soglia
Carolyn B
CB
Treadway
Judith L
JL
VanVolkenburg
Maria A
MA
Wilder
Donald C
DC
Piotrowski
David W
DW
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
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