Sulfamide-based inhibitors for carboxypeptidase A. novel type transition state analogue inhibitors for zinc proteases

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Title
Sulfamide-based inhibitors for carboxypeptidase A. novel type transition state analogue inhibitors for zinc proteases
Author(s)
J D Park; D H Kim; Seung-Jun Kim; J R Woo; Seong Eon Ryu
Bibliographic Citation
Journal of Medicinal Chemistry, vol. 45, no. 24, pp. 5295-5302
Publication Year
2002
Abstract
N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the terminal amino group were designed rationally as transition state analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the Ki value of 0.64 μM. Its enantiomer was shown to be much less potent (Ki = 470 μM). Introduction of an alkyl group such as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the inhibitory potency drastically. Introduction of a methyl group on the internal amino group of (S)-1a also caused a drastic reduction of the inhibitory activity. The structure of the CPA-(S)-1a complex determined by single-crystal X-ray diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and functional groups at the active site of CPA, which is reminiscent of the postulated stabilization mode of a tetrahedral transition state in the CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis, the present inhibitors are inferred to be a novel type of transition state analogue inhibitor for CPA.
ISSN
0022-2623
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/jm020258v
Type
Article
Appears in Collections:
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
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