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

Powell NA, Ciske FL, Cai C, Holsworth DD, Mennen K, Van Huis CA, Jalaie M, Day J, Mastronardi M, McConnell P, Mochalkin I, Zhang E, Ryan MJ, Bryant J, Collard W, Ferreira S, Gu C, Collins R, Edmunds JJ

Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. powellns@netzero.com

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.

Published 16 July 2007 in Bioorg Med Chem, 15(17): 5912-49.
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