Title of article :
Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors Original Research Article
Author/Authors :
Noel A. Powell، نويسنده , , Fred L. Ciske، نويسنده , , Cuiman Cai، نويسنده , , Daniel D. Holsworth، نويسنده , , Ken Mennen، نويسنده , , Chad A. Van Huis، نويسنده , , Mehran Jalaie، نويسنده , , Jacqueline Day، نويسنده , , Michelle Mastronardi، نويسنده , , Pat McConnell، نويسنده , , Igor Mochalkin، نويسنده , , Erli Zhang، نويسنده , , MICHAEL J. RYAN، نويسنده , , john bryant، نويسنده , , Wendy Collard، نويسنده , , Suzie Ferreira، نويسنده , , Chungang Gu، نويسنده , , Roxane Collins، نويسنده , , Jeremy J. Edmunds، نويسنده ,
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 S3sp subsite.
Keywords :
Oral bioavailability , structure-based drug design , Renin , Hypertension
