Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles.

Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Research Abstract Details 

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Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Abstract Text:

R Edward Watts,Mathew Siegel,Chaitan Khosla,

Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.

Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Publishing Authors By Initials

RE Watts,M Siegel,C Khosla,

For similar enzymes and coenzymes: enzymes: transferases: acyltransferases: aminoacyltransferases: transglutaminases research abstracts see: enzymes and coenzymes: enzymes: transferases: acyltransferases: aminoacyltransferases: transglutaminases research

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Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of medicinal chemistry

VOLUME: 49

Page Numbers: 7493-501

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 14

MONTH: Dec

YEAR: 2006

Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9716531

Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Keywords Mesh Terms:

KEYWORDS: Transglutaminases

MESH TERMS: chemistry

Chemical & Substance for Abstract: Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles. Information

Substance Name: GTP-Binding Proteins

Registry Number: EC 3.6.1.-

Grant and Affiliation Information for Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles.

AFFILIATION: Department of Chemistry, Stanford University, Stanford, California 94305, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: R01 DK 063158

ACRONYM: DK

MEDLINETA: J Med Chem

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