Synthesis and evaluation of alpha,alpha-disubstituted-3-mercaptopropanoic acids as inhibitors for carboxypeptidase A and implications with respect to enzyme inhibitor design

Bioorg Med Chem. 2003 Nov 3;11(22):4685-91. doi: 10.1016/j.bmc.2003.08.017.

Abstract

2-Ethyl-2-methyl-3-mercaptopropanoic acid (6) and 2-benzyl-2-methyl-3-mercaptopropanoic acid (7) were synthesized and evaluated as inhibitors for carboxypeptidase A (CPA), a prototypical zinc protease with the expectation that the binding affinities of these inhibitors would be augmented over those of 2-ethyl-3-methylsuccinic acid (2) and 2-benzyl-3-methylsuccinic acid (3), respectively, in light of the fact that the sulfhydryl group is a better zinc coordinating moiety than the carboxylate group. Contrary to the expectation, however, the inhibitory potency of 6 was not improved and that of 7 was rather attenuated by the replacement. A probable explanation for the unexpected results is offered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxypeptidases A / antagonists & inhibitors*
  • Cattle
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Kinetics
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology*

Substances

  • Enzyme Inhibitors
  • Propionates
  • Sulfhydryl Compounds
  • Carboxypeptidases A