No abstract

A series of derivatives of (phenylsulfanyl)benzoic acids bearing quinoline, 2,4-dihydroxy-3-propylacetophenone and 2,4-difluorobiphenyl moieties were prepared and their antileukotrienic activities evaluated. Some of the compounds were found to display multiple antileukotrienic effect in the inhibition of LTB4biosynthesis, binding to LTD4and LTB4receptors, superior to the standards (zileuton and zafirlukast) used. The compounds had an antiinflammatory effect, manifested with quinoline derivatives by a significant inhibition of bronchospasm induced by LTD4and/or albumin. The results of regression analysis correspond to the observation that the most active compounds belong to quinoline derivatives with the lowest lipophilicity. X-ray analysis of the quinoline compounds revealed that an intramolecular hydrophobic interaction of their aromatic rings does not occur in the solid state.

Dedicated to the 50th anniversary of the foundation of the Department of Biochemistry, the first biochemical department in Czechoslovakia.The phase I metabolism of quinlukast (VÚFB 19363, Q; 4-{[4-(2-quinolylmethoxy)phenyl]-sulfanyl}benzoic acid), a new antiasthmatic drug with significant antileukotriene effects, was investigated in rat microsomes and hepatocytes. Quinlukast, incubated with rat liver microsomal fraction under oxidative conditions, generated four metabolites, M2-M5. Based on comparison with synthetically prepared standards, metabolites M2 and M4 were identified as sulfoxide and sulfone of the parent compound, respectively. Metabolites M3 and M5 were identified as quinlukast dihydrodiols. For all the metabolites the apparent kinetic parameters ′ K m , ′ V max and metabolic efficiency Cl int were calculated. No metabolite was found in rat liver cytosol. In vitro studies with primary cultures of isolated hepatocytes were designed to evaluate time dependent (2, 4, 8 and 24 h) and concentration dependent (0.005-0.1 mmol/l) formation of metabolites of quinlukast. Four metabolites were detected in culture medium. Three of them were identical to metabolites found in incubation of quinlukast with microsomes (M2, M3 and M5) and another, the most polar metabolite, M1, was detected. The basic metabolic pathways were proposed for quinlukast in rats.

A series of 3-fluro-4-alkoxyphenylalkanoic acids III was synthetized and their antiinflammatory activity and fibrinolytic capacity was evaluated. The suitable fluorinated derivative with better pharmacological profile than 3-chloro-4-benzyloxyphenylacetic acid (benzofenac) was selected. Experimental, biological activities of acids III were compared with those calculated by introducing the physico-chemical parameters into the formerly derived regression equations. Good coincidence was found out, as well as similarity of the regression derived for the original series of acids extended by the acids III. Lipophilicity of the acids under study was evaluated by partition thin-layer chromatography; the values of log P of benzyloxy derivatives IIIc-IIIf were lower than tabulated values - probably due to the intramolecular hydrophobic interactions of aromatic nuclei.

A series of substituted cyclohexylacetic acids I has been obtained by hydrogenation of the unsaturated analogues II and III. Esters of these analogues were prepared by the Horner-Wittig reaction of the corresponding cyclohexanones IV and/or 2-cyclohexenones V with triethyl phosphonoacetate. These esters were obtained in two isomeric forms (Z and E), differing in the double bond in the exo-position. The derivatives with a substituent in the 2-position exhibited a partial shift of the double bond to the cyclohexane ring; this shift was especially marked in the 2-phenyl derivative. With the acids I-III, activation of fibrinolysis was assessed by the hanging clot method; the anti-inflammatory effect was assessed by inhibition of two experimental model inflammations. The regression equation relating fibrinolytic capacity to lipophilicity was a quadratic one, the logarithm of optimum lipophilicity being log Popt = 5.55. A qualitative assessment of the anti-inflammatory effect in relation to lipophilicity suggests that log Popt is probably higher than with arylaliphatic acids. These acids seem to have an active site different from that of the acids I-III.