PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 15279599

New developments on thromboxane modulators.

Jean-Michel Dogné·Julien Hanson·Xavier de Leval·Bernard Masereel·Philippe Kolh·Bernard Pirotte
View original source ↗Export metadata ↓

Abstract

Thromboxane A(2) (TXA(2)) is a labile product formed from arachidonic acid by cyclooxygenase. The pathogenesis of numerous cardiovascular, pulmonary, and thromboembolic diseases can be related to this metabolite. Therefore, TXA(2) modulators have been developed for 20 years. This review will highlight the evolution in the field of TXA(2) modulators.

Explore related subjects

Enzyme InhibitorsHumansReceptors, ThromboxaneSignal TransductionThromboxane A2Thromboxane-A SynthaseJournal ArticleResearch Support, Non-U.S. Gov'tReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Jean-Michel Dogné, Julien Hanson, Xavier de Leval, Bernard Masereel, Philippe Kolh, Bernard Pirotte. 2004. New developments on thromboxane modulators.. https://doi.org/10.2174/1389557043403684

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2004

Design, synthesis, and evaluation of acyclic C-nucleoside and N-methylated derivatives of the ribitylaminopyrimidine substrate of lumazine synthase as potential enzyme inhibitors and mechanistic probes.

Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin, a vitamin that is involved in many critical biochemical reactions that are essential for the maintenance of life. To obtain inhibitors and structural probes that could be useful in studying the structures of bound reaction intermediates, the ribitylamino N-H moiety of the lumazine synthase substrate was replaced by CH(2) and N-CH(3) groups. The CH(2) replacement unexpectedly and completely abolished the affinity for lumazine synthase, thus revealing a critical, yet unexplained, role of the ribitylamino N-H moiety in conferring affinity for the enzyme. In contrast, the N-CH(3) replacement resulted in an inhibitor of both lumazine synthase and riboflavin synthase. Replacement of the ribitylamino N-H moiety with epimeric C-F moieties led to inhibition of lumazine synthase and riboflavin synthase when combined with the replacement of the 5-amino group with a nitro substituent.

Enzyme Inhibitors↗
PubMed2004

The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.

4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.

Enzyme Inhibitors↗
PubMed2004

Synthesis and high-throughput screening of N-acetyl-beta-hexosaminidase inhibitor libraries targeting osteoarthritis.

C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.

Enzyme Inhibitors↗