Abstract
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
MeSH terms
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Biological Availability
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Blood Proteins / metabolism
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Carboxypeptidases / antagonists & inhibitors*
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Carboxypeptidases / genetics
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Drug Design
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Humans
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Male
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Mice
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Mice, Knockout
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Obesity / drug therapy
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Obesity / enzymology
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemical synthesis
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Phenylalanine / pharmacokinetics
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Phenylalanine / pharmacology
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Protein Binding
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-amino-N-(3-(biphenyl-4-yl)-1-(2-(5,6-dichloro-1H-benzimidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-2-methylpropanamide
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Anti-Obesity Agents
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Benzimidazoles
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Blood Proteins
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Serine Proteinase Inhibitors
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Phenylalanine
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Carboxypeptidases
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lysosomal Pro-X carboxypeptidase