Abstract
Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).
MeSH terms
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Aminobutyrates / chemical synthesis*
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Aminobutyrates / chemistry
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Aminobutyrates / pharmacology
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Animals
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Biological Availability
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Dipeptidyl Peptidase 4 / metabolism*
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Half-Life
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Methylation
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Rats
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Aminobutyrates
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Protease Inhibitors
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Thiazoles
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2-amino-4-phenylbutyric acid
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Dipeptidyl Peptidase 4