RP-64966

The synthesis and structure-activity profile of a new class of potent and specific LTA4 hydrolase inhibitors are described. Many compounds of this series of omega-[5-(omega-arylalkyl)-2-thienyl]- and omega-[4-(omega-arylalkyl)phenyl]alkanoic acids were found to be potent in vitro inhibitors of the LTB4 production by porcine leukocytes with IC50 ranging from 1 to 10 microM. The side-chain lengths were critical for an optimal activity. Substitutions on the terminal aromatic ring, in the benzene series, by lipophilic and electron-donating substituents substantially enhanced the LTA4 hydrolase inhibition potency. On the other hand, in the thiophene series, the effect of of such substitutions on the LTA4 hydrolase inhibition was rather small. Functionalization within the carboxylic acid side chain by a carbonyl or by a hydroxyl group led to less potent compounds. A metabolically stable LTA4 hydrolase inhibitor, RP64966, was obtained by insertion of an oxygen atom in the beta-position on the carboxylic acid side chain. After oral administration of RP64966 to rats, a plasma extract was found to display potent inhibition of the LTB4 biosynthesis (40% inhibition at 5 mg/kg, po).