title: Ridogrel: a selective inhibitor of the cytochrome P450-dependent thromboxane synthesis.
abstract: Ridogrel [(E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl] methylene]amino]oxy] pentanoic acid] is a potent inhibitor of the P450-dependent human platelet thromboxane A2 (TxA2) synthase. Fifty percent inhibition is already achieved at 5.0 +/- 0.37 nM. This IC50 value is close to half the P450 concentration used, i.e. 10.7 nM. Ridogrel binds to human platelet microsomal P450 as proven by the type II spectral changes induced by the addition of increasing concentrations of ridogrel to solubilized microsomes. The calculated half-maximal spectral change (SC50 value) is 3.78 +/- 1.79 nM. These results indicate that ridogrel binds stoichiometrically and suggest that inhibition of thromboxane synthesis may originate from liganding of its basic nitrogen to the haem-iron of P450 and from the attachment of the hydrophobic carboxylic side chain to or near the substrate binding place. Ridogrel is a selective inhibitor of the TxA2 synthase. At a high concentration (10 microM), ridogrel has a slight, if any, effect on the P450-mediated cholesterol synthesis in human liver and hepatoma cells and androgen synthesis from 17 alpha-hydroxy-20-dihydroprogesterone or pregnenolone in subcellular fractions from rat testes. These results indicate that ridogrel is a poor inhibitor of the P450-dependent 14 alpha-demethylase, 17 alpha-hydroxylase and 17,20-lyase. It has, up to 10 microM, no effect on the adrenal mitochondrial 11 beta-hydroxylase and cholesterol side-chain cleavage enzyme and does not inhibit aromatase activity in human placental microsomes. Ridogrel has no significant effect on the regio- and stereoselective P450-dependent oxidations of testosterone in liver microsomes from unpretreated or from 5-pregnen-3 beta-ol-20-one-16 alpha-carbonitrile-, phenobarbital- or 3-methylcholanthrene-pretreated male and female Sprague-Dawley rats. It does not interfere with the reduction of testosterone into 5 alpha-dihydrotestosterone and 5 alpha androstane 3 beta, 17 beta-diol.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Vanden Bossche
authors.forename: G
authors.initials: G
authors.lastname: Willemsens
authors.forename: D
authors.initials: D
authors.lastname: Bellens
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002784:Cholesterol / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008861:Microsomes / Q000187:drug effects; D010421:Pentanoic Acids / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions / Q000201:enzymology; D013739:Testosterone / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000728:Androgens; D065607:Cytochrome P-450 Enzyme Inhibitors; D010421:Pentanoic Acids; D011725:Pyridines; D013739:Testosterone; D013928:Thromboxane A2; D002784:Cholesterol; D013930:Thromboxane-A Synthase; C060219:ridogrel