Thromboxane A2 biosynthesis inhibitors: synthesis and evaluation of pyrazolotriazinyl alkanoic acids
| Autor: | J. Couquelet, C. Navarro-Delmasure, A. Pham Huu Chanh, B. Lasserre, S. Mavel, V. Dossou-Gbete, Coudert P |
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| Rok vydání: | 1994 |
| Předmět: |
Blood Platelets
Models Molecular Thromboxane Stereochemistry Clinical Biochemistry Prostaglandin chemistry.chemical_compound Thromboxane A2 Structure-Activity Relationship Biosynthesis Microsomes Animals Prostaglandins H Horses Arachidonic Acid biology Bicyclic molecule Dose-Response Relationship Drug Triazines Cell Biology Thromboxane B2 Biochemistry chemistry Enzyme inhibitor biology.protein Prostaglandin H2 Arachidonic acid Thromboxane-A synthase Thromboxane-A Synthase |
| Zdroj: | Prostaglandins, leukotrienes, and essential fatty acids. 51(3) |
| ISSN: | 0952-3278 |
| Popis: | A novel series of (6-aryl-4-oxo-pyrazolo 2,3-d] [1,2,5] triazin-3-yl) alkanoic acids was synthesized and evaluated in vitro as thromboxane A 2 (TXA 2 ) biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 μM) as a substrate and horse platelet microsomes (HPM) as sources of TXA 2 synthetase. TXB 2 , a stable breakdown product of TXA 2 , was determined by radioimmunoassays (RIA). The substances under study, at concentrations ranging from 1.10 −6 M to 1.10 −4 M, significantly inhibited the biosynthesis of TXA 2 in vitro. This activity was found to be dose-dependent, the potency of which could be related to structural features of the molecules. Compound 3b, bearing a butanoic side chain in the 3-position and a 4-chloro phenyl ring in the 6-position of the bicyclic system, was the most active derivative in in vitro enzyme inhibition (ID 50 = 2.81 × 10 −5 M). Comparison of the spatial configurations of prostaglandin H 2 (PGH 2 ) and 3b displayed a good correlation between essential structural moieties of both molecules. In addition, a conceptual model for the PGH 2 and TX synthetase interactions was applied to compound 3b. |
| Databáze: | OpenAIRE |
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