Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors |
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| Authors: | Powell Noel A Ciske Fred L Cai Cuiman Holsworth Daniel D Mennen Ken Van Huis Chad A Jalaie Mehran Day Jacqueline Mastronardi Michelle McConnell Pat Mochalkin Igor Zhang Erli Ryan Michael J Bryant John Collard Wendy Ferreira Suzie Gu Chungang Collins Roxane Edmunds Jeremy J |
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| Institution: | Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. powellns@netzero.com |
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| 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. |
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