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Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates

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dc.contributor Wichita State University. Department of Chemistry en_US
dc.contributor.author Kuang, Rongze en_US
dc.contributor.author Epp, Jeffrey B. en_US
dc.contributor.author Ruan, Sumei en_US
dc.contributor.author Chong, Lee S. en_US
dc.contributor.author Venkataraman, Radhika en_US
dc.contributor.author Tu, Juan en_US
dc.contributor.author He, Shu en_US
dc.contributor.author Truong, Tien M. en_US
dc.contributor.author Groutas, William C. en_US
dc.date.accessioned 2012-02-06T17:16:47Z
dc.date.available 2012-02-06T17:16:47Z
dc.date.issued 2000-05-01 en_US
dc.identifier 10882012 en_US
dc.identifier 9413298 en_US
dc.identifier S0968-0896(00)00038-9 en_US
dc.identifier HL 57788 en_US
dc.identifier.citation Bioorganic & medicinal chemistry. 2000 May; 8(5): 1005-16. en_US
dc.identifier.issn 0968-0896 en_US
dc.identifier.uri http://hdl.handle.net/10057/4347
dc.description Full text of this article is not available in SOAR. en_US
dc.description.abstract A series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synthesized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then determined. Most of the compounds were found to be potent, time-dependent inhibitors of elastase, with some of the compounds exhibiting k(inact)/K1 values as high as 4,928,300 M(-1) s(-1). The inhibitory potency of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide platform was found to be influenced by both the pKa and the inherent structure of the leaving group. Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently. The predictable mode of binding of these compounds suggests that, among closely-related serine proteases, highly selective inhibitors of a particular serine protease can be fashioned by exploiting subtle differences in their S' subsites. This study has also demonstrated that the degradative action of elastase on elastin can be abrogated in the presence of inhibitor 17. en_US
dc.description.sponsorship NHLBI NIH HHS en_US
dc.format.extent 1005-16 en_US
dc.language.iso eng en_US
dc.publisher Elsevier en_US
dc.relation.ispartofseries Bioorganic & medicinal chemistry en_US
dc.relation.ispartofseries Bioorg. Med. Chem. en_US
dc.source NLM en_US
dc.subject Research Support, Non-U.S. Gov't en_US
dc.subject Research Support, U.S. Gov't, P.H.S. en_US
dc.subject.mesh Cyclic S-Oxides/chemistry en_US
dc.subject.mesh Drug Design en_US
dc.subject.mesh Elastin/metabolism en_US
dc.subject.mesh Humans en_US
dc.subject.mesh Magnetic Resonance Spectroscopy en_US
dc.subject.mesh Models, Molecular en_US
dc.subject.mesh Serine Proteinase Inhibitors/chemistry en_US
dc.subject.mesh Structure-Activity Relationship en_US
dc.subject.mesh Thiadiazoles/chemistry en_US
dc.subject.mesh Serine Proteinase Inhibitors/metabolism en_US
dc.subject.mesh Serine Proteinase Inhibitors/pharmacology en_US
dc.title Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates en_US
dc.type Article en_US
dc.coverage.spacial England en_US
dc.description.version peer reviewed en_US
dc.rights.holder Copyright © 2000, Elsevier en_US

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