Discovery of 6-ethyl-2,4-diaminopyrimidine-based small molecule renin inhibitors.
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Holsworth
Daniel D
DD
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Daniel.Holsworth@pfizer.com <Daniel.Holsworth@pfizer.com>
Jalaie
Mehran
M
Belliotti
Thomas
T
Cai
Cuiman
C
Collard
Wendy
W
Ferreira
Suzie
S
Powell
Noel A
NA
Stier
Michael
M
Zhang
Erli
E
McConnell
Pat
P
Mochalkin
Igor
I
Ryan
Michael J
MJ
Bryant
John
J
Li
Tingsheng
T
Kasani
Aparna
A
Subedi
Rajendra
R
Maiti
Samarendra N
SN
Edmunds
Jeremy J
JJ
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D011743:Pyrimidines; D000092502:Renin Inhibitors; C017205:2,4-diaminopyrimidine