title: Discovery of 6-ethyl-2,4-diaminopyrimidine-based small molecule renin inhibitors.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Daniel.Holsworth@pfizer.com <Daniel.Holsworth@pfizer.com>
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Thomas
authors.initials: T
authors.lastname: Belliotti
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: Wendy
authors.initials: W
authors.lastname: Collard
authors.forename: Suzie
authors.initials: S
authors.lastname: Ferreira
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.forename: Michael
authors.initials: M
authors.lastname: Stier
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Pat
authors.initials: P
authors.lastname: McConnell
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: John
authors.initials: J
authors.lastname: Bryant
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Li
authors.forename: Aparna
authors.initials: A
authors.lastname: Kasani
authors.forename: Rajendra
authors.initials: R
authors.lastname: Subedi
authors.forename: Samarendra N
authors.initials: SN
authors.lastname: Maiti
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: 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
chemical_list: D011743:Pyrimidines; D000092502:Renin Inhibitors; C017205:2,4-diaminopyrimidine