title: Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors.
abstract: We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.
authors.affiliation: Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. powellns@netzero.com
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.forename: Fred L
authors.initials: FL
authors.lastname: Ciske
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Ken
authors.initials: K
authors.lastname: Mennen
authors.forename: Chad A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Day
authors.forename: Michelle
authors.initials: M
authors.lastname: Mastronardi
authors.forename: Pat
authors.initials: P
authors.lastname: McConnell
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: John
authors.initials: J
authors.lastname: Bryant
authors.forename: Wendy
authors.initials: W
authors.lastname: Collard
authors.forename: Suzie
authors.initials: S
authors.lastname: Ferreira
authors.forename: Chungang
authors.initials: C
authors.lastname: Gu
authors.forename: Roxane
authors.initials: R
authors.lastname: Collins
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000586:Amination; D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D048588:Benzoxazines; D011725:Pyridines; D012083:Renin; D000092502:Renin Inhibitors; C023666:pyridine