Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
Pei
Zhonghua
Z
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. zhonghua.pei@abbott.com
Li
Xiaofeng
X
von Geldern
Thomas W
TW
Madar
David J
DJ
Longenecker
Kenton
K
Yong
Hong
H
Lubben
Thomas H
TH
Stewart
Kent D
KD
Zinker
Bradley A
BA
Backes
Bradley J
BJ
Judd
Andrew S
AS
Mulhern
Mathew
M
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Mika
Amanda K
AK
Beno
David W A
DW
Reinhart
Glenn A
GA
Fryer
Ryan M
RM
Preusser
Lee C
LC
Kempf-Grote
Anita J
AJ
Sham
Hing L
HL
Trevillyan
James M
JM
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D053138:Cyclohexenes / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D011924:Rats, Zucker; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014961:X-Ray Diffraction
C515232:ABT 341; D001713:Biphenyl Compounds; D053138:Cyclohexenes; D007004:Hypoglycemic Agents; D015842:Serine Proteinase Inhibitors; D014230:Triazoles; C052568:cyclohexene; D018819:Dipeptidyl Peptidase 4