Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Madar
David J
DJ
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6001, USA. david.madar@abbott.com
Kopecka
Hana
H
Pireh
Daisy
D
Yong
Hong
H
Pei
Zhonghua
Z
Li
Xiaofeng
X
Wiedeman
Paul E
PE
Djuric
Stevan W
SW
Von Geldern
Thomas W
TW
Fickes
Michael G
MG
Bhagavatula
Lakshmi
L
McDermott
Todd
T
Wittenberger
Steven
S
Richards
Steven J
SJ
Longenecker
Kenton L
KL
Stewart
Kent D
KD
Lubben
Thomas H
TH
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Long
Michelle A
MA
Wells
Heidi
H
Zinker
Bradley A
BA
Mika
Amanda K
AK
Beno
David W A
DW
Kempf-Grote
Anita J
AJ
Polakowski
James
J
Segreti
Jason
J
Reinhart
Glenn A
GA
Fryer
Ryan M
RM
Sham
Hing L
HL
Trevillyan
James M
JM
D000243:Adenosine Deaminase / Q000737:chemistry; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C515139:2-(4-((2-(2-cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethyl)amino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid; D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D011725:Pyridines; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase