Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors.
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.
Powell
Noel A
NA
Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. powellns@netzero.com
Ciske
Fred L
FL
Cai
Cuiman
C
Holsworth
Daniel D
DD
Mennen
Ken
K
Van Huis
Chad A
CA
Jalaie
Mehran
M
Day
Jacqueline
J
Mastronardi
Michelle
M
McConnell
Pat
P
Mochalkin
Igor
I
Zhang
Erli
E
Ryan
Michael J
MJ
Bryant
John
J
Collard
Wendy
W
Ferreira
Suzie
S
Gu
Chungang
C
Collins
Roxane
R
Edmunds
Jeremy J
JJ
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
D048588:Benzoxazines; D011725:Pyridines; D012083:Renin; D000092502:Renin Inhibitors; C023666:pyridine