Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Meng
Wei
W
Departments of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, Princeton, New Jersey 08543-5400, USA. wei.meng@bms.com
Brigance
Robert P
RP
Chao
Hannguang J
HJ
Fura
Aberra
A
Harrity
Thomas
T
Marcinkeviciene
Jovita
J
O'Connor
Stephen P
SP
Tamura
James K
JK
Xie
Dianlin
D
Zhang
Yaqun
Y
Klei
Herbert E
HE
Kish
Kevin
K
Weigelt
Carolyn A
CA
Turdi
Huji
H
Wang
Aiying
A
Zahler
Robert
R
Kirby
Mark S
MS
Hamann
Lawrence G
LG
D000818:Animals; D020134:Catalytic Domain; 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; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C551946:6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo(1,2-a)pyrimidine-2-carboxamide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; D007093:Imidazoles; C000606913:KCNH2 protein, human; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse