Synthesis and evaluation of alpha,alpha-disubstituted-3-mercaptopropanoic acids as inhibitors for carboxypeptidase A and implications with respect to enzyme inhibitor design.
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.
Lee
Hyun Soo
HS
Center for Integrated Molecular Systems, Pohang University of Science and Technology, San 31 Hyojadong, 790-784 Pohang, South Korea.
Kim
Dong H
DH
D000818:Animals; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors*; D002417:Cattle; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011422:Propionates; D013438:Sulfhydryl Compounds; D043422:Carboxypeptidases A