cis-2,5-dicyanopyrrolidine inhibitors of dipeptidyl peptidase IV: synthesis and in vitro, in vivo, and X-ray crystallographic characterization.
Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.
Wright
Stephen W
SW
Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. stephen.w.wright@pfizer.com
Ammirati
Mark J
MJ
Andrews
Kim M
KM
Brodeur
Anne M
AM
Danley
Dennis E
DE
Doran
Shawn D
SD
Lillquist
Jay S
JS
McClure
Lester D
LD
McPherson
R Kirk
RK
Orena
Stephen J
SJ
Parker
Janice C
JC
Polivkova
Jana
J
Qiu
Xiayang
X
Soeller
Walter C
WC
Soglia
Carolyn B
CB
Treadway
Judith L
JL
VanVolkenburg
Maria A
MA
Wang
Hong
H
Wilder
Donald C
DC
Olson
Thanh V
TV
D000243:Adenosine Deaminase / Q000737:chemistry*; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D004285:Dogs; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C511630:1-(((1-(hydroxymethyl)cyclopentyl)amino)acetyl)pyrrolidine-2,5-dicarbonitrile; D058892:Adenosine Deaminase Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase