title: Thromboxane A2 biosynthesis inhibitors: synthesis and evaluation of pyrazolotriazinyl alkanoic acids.
abstract: 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 A2 (TXA2) biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes (HPM) as sources of TXA synthetase. TXB2, a stable breakdown product of TXA2, 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 TXA2 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 (ID50 = 2.81 x 10(-5) M). Comparison of the spatial configurations of prostaglandin H2 (PGH2 and 3b displayed a good correlation between essential structural moieties of both molecules. In addition, conceptual model for the PGH2 and TX synthetase interactions was applied to compound 3b.
authors: Institut de Physiologie, Université P. Sabatier- 2F, Toulouse, France.
authors: B
authors: B
authors: Lasserre
authors: S
authors: S
authors: Mavel
authors: P
authors: P
authors: Coudert
authors: A
authors: A
authors: Pham Huu Chanh
authors: C
authors: C
authors: Navarro-Delmasure
authors: V
authors: V
authors: Dossou-Gbete
authors: J
authors: J
authors: Couquelet
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D006736:Horses / Q000097:blood; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000032:analysis; D013930:Thromboxane-A Synthase / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011463:Prostaglandins H; D014227:Triazines; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D013929:Thromboxane B2; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase