1. Optimization of orally bioavailable alkyl amine renin inhibitors.
- Author
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Xu Z, Cacatian S, Yuan J, Simpson RD, Jia L, Zhao W, Tice CM, Flaherty PT, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Bentley R, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, and Claremon DA
- Subjects
- Administration, Oral, Amines chemical synthesis, Amines pharmacokinetics, Animals, Binding Sites, Blood Pressure drug effects, Carbamates chemical synthesis, Carbamates pharmacokinetics, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Haplorhini, Humans, Piperidines chemical synthesis, Piperidines pharmacokinetics, Rats, Rats, Transgenic, Renin blood, Renin metabolism, Structure-Activity Relationship, Amines chemistry, Carbamates chemistry, Enzyme Inhibitors chemistry, Piperidines chemistry, Renin antagonists & inhibitors
- Abstract
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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