Optimization of orally bioavailable alkyl amine renin inhibitors

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 0.83 nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10 mg/kg resulted in >20 h reduction of blood pressure in a d...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.694-699
Hauptverfasser:	Xu, Zhenrong, Cacatian, Salvacion, Yuan, Jing, Simpson, Robert D., Jia, Lanqi, Zhao, Wei, Tice, Colin M., Flaherty, Patrick T., Guo, Joan, Ishchenko, Alexey, Singh, Suresh B., Wu, Zhongren, McKeever, Brian M., Scott, Boyd B., Bukhtiyarov, Yuri, Berbaum, Jennifer, Mason, Jennifer, Panemangalore, Reshma, Cappiello, Maria Grazia, Bentley, Ross, Doe, Christopher P., Harrison, Richard K., McGeehan, Gerard M., Dillard, Lawrence W., Baldwin, John J., Claremon, David A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral AMINES Amines - chemical synthesis Amines - chemistry Amines - pharmacokinetics Animals Antihypertensive agents Aspartyl protease BASIC BIOLOGICAL SCIENCES Binding Sites Biological and medical sciences BLOOD PRESSURE Blood Pressure - drug effects Carbamates - chemical synthesis Carbamates - chemistry Carbamates - pharmacokinetics Cardiovascular system Crystallography, X-Ray DESIGN Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE Haplorhini Humans HYPERTENSION IN VITRO IN VIVO LEAD COMPOUNDS Medical sciences OPTIMIZATION ORAL ADMINISTRATION Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacokinetics PLASMA Rats Rats, Transgenic RENIN Renin - antagonists & inhibitors Renin - blood Renin - metabolism Structure-Activity Relationship Structure-based drug design X-ray crystallography
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Zusammenfassung:	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 0.83 nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10 mg/kg resulted in >20 h reduction of blood pressure in a double transgenic rat model of hypertension.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.11.066