Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
Backes
Bradley J
BJ
Metabolic Disease Research, Abbott Laboratories, Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com
Longenecker
Kenton
K
Hamilton
Gregory L
GL
Stewart
Kent
K
Lai
Chunqiu
C
Kopecka
Hana
H
von Geldern
Thomas W
TW
Madar
David J
DJ
Pei
Zhonghua
Z
Lubben
Thomas H
TH
Zinker
Bradley A
BA
Tian
Zhenping
Z
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Mika
Amanda K
AK
Beno
David W A
DW
Kempf-Grote
Anita J
AJ
Black-Schaefer
Candace
C
Sham
Hing L
HL
Trevillyan
James M
JM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D053138:Cyclohexenes / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
D001786:Blood Glucose; D053138:Cyclohexenes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D011759:Pyrrolidines; C052568:cyclohexene; C032519:pyrrolidine