Design and optimization of renin inhibitors: Orally bioavailable alkyl amines

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC 50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypert...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-07, Vol.19 (13), p.3541-3545
Main Authors: Tice, Colin M., Xu, Zhenrong, Yuan, Jing, Simpson, Robert D., Cacatian, Salvacion T., Flaherty, Patrick T., Zhao, Wei, Guo, Joan, Ishchenko, Alexey, Singh, Suresh B., Wu, Zhongren, Scott, Boyd B., Bukhtiyarov, Yuri, Berbaum, Jennifer, Mason, Jennifer, Panemangalore, Reshma, Cappiello, Maria Grazia, Müller, Dominik, Harrison, Richard K., McGeehan, Gerard M., Dillard, Lawrence W., Baldwin, John J., Claremon, David A.
Format: Article
Language:English
Subjects:
Administration, Oral
AMINES
Amino Acid Sequence
Animals
Antihypertensive
Antihypertensive agents
Antihypertensive Agents - chemical synthesis
Antihypertensive Agents - chemistry
Antihypertensive Agents - pharmacokinetics
Aspartyl protease
BASIC BIOLOGICAL SCIENCES
Biological and medical sciences
BLOOD PRESSURE
Cardiovascular system
Computer Simulation
Crystallography, X-Ray
DESIGN
Drug Design
DRUGS
GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
Humans
HYPERTENSION
LEAD COMPOUNDS
Medical sciences
Methylamines - chemical synthesis
Methylamines - chemistry
Methylamines - pharmacokinetics
national synchrotron light source
OPTIMIZATION
ORAL ADMINISTRATION
Pharmacology. Drug treatments
RATS
Rats, Transgenic
REDUCTION
RENIN
Renin - antagonists & inhibitors
Renin - metabolism
Structure based drug design
Structure-Activity Relationship
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Description
Summary:Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC 50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2009.04.140