Abstract
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
MeSH terms
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Crystallography, X-Ray
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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Piperazines / chemical synthesis
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Piperazines / chemistry*
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Piperazines / pharmacology*
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Renin / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Piperazines
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Cytochrome P-450 Enzyme System
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Renin