Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.
The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.
Corbett
J W
JW
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Dirico
K
K
Song
W
W
Boscoe
B P
BP
Doran
S D
SD
Boyer
D
D
Qiu
X
X
Ammirati
M
M
Vanvolkenburg
M A
MA
McPherson
R K
RK
Parker
J C
JC
Cox
E D
ED
D000586:Amination; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D003486:Cyanides / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003486:Cyanides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011758:Pyrroles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D001554:Benzene