New fluorinated pyrrolidine and azetidine amides as dipeptidyl peptidase IV inhibitors.
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
Hulin
Bernard
B
Pfizer Global Research and Development, Groton, CT 06340, USA. bernard.hulin@pfizer.com
Cabral
Shawn
S
Lopaze
Michael G
MG
Van Volkenburg
Maria A
MA
Andrews
Kim M
KM
Parker
Janice C
JC
D058892:Adenosine Deaminase Inhibitors; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001384:Azetidines; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4; D004195:Disease Models, Animal; D005461:Fluorine; D005951:Glucose Tolerance Test; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D058892:Adenosine Deaminase Inhibitors; D000577:Amides; D001384:Azetidines; D006023:Glycoproteins; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D005461:Fluorine; C082735:azetidine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4