Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors.

Noel A Powell, Fred L Ciske, Cuiman Cai, Daniel D Holsworth, Ken Mennen, Chad A Van Huis, Mehran Jalaie, Jacqueline Day, Michelle Mastronardi, Pat McConnell, Igor Mochalkin, Erli Zhang, Michael J Ryan, John Bryant, Wendy Collard, Suzie Ferreira, Chungang Gu, Roxane Collins, Jeremy J Edmunds

文献索引：Bioorg. Med. Chem. 15 , 5912, (2007)

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摘要

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.