期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 13, 页码 3970-3975出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.05.013
关键词
Renin; Inhibitor; Anti-hypertensive
An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.
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