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Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of pyridone-substituted piperidines
- Source :
- Bioorganicmedicinal chemistry letters. 21(13)
- Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Models, Molecular
medicine.drug_class
Stereochemistry
Pyridones
Clinical Biochemistry
Pharmaceutical Science
Pharmacology
Biochemistry
Renin inhibitor
Chemical synthesis
chemistry.chemical_compound
Inhibitory Concentration 50
Structure-Activity Relationship
Dogs
Piperidines
In vivo
Drug Discovery
Renin–angiotensin system
Renin
medicine
Structure–activity relationship
Animals
Enzyme Inhibitors
Molecular Biology
biology
Molecular Structure
Organic Chemistry
Rats
chemistry
Enzyme inhibitor
Drug Design
Lipophilicity
Hypertension
Lactam
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 21
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....6984bb7f944791450d3c0856db18d4c4