BICYCLIC N-HYDROXYUREA INHIBITORS OF 5-LIPOXYGENASE - PHARMACODYNAMIC, PHARMACOKINETIC, AND IN-VITRO METABOLIC STUDIES CHARACTERIZING (2,3-DIHYDRO-6-(PHENYLMETHOXY)-3-BENZOFURANYL)UREA

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by exam ining the inhibition of LTB(4) biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compo unds was assessed using an ex vivo LTB(4) assay and an adoptive perito neal anaphylaxis assay at extended pretreat times. Compounds with an e xtended duration of action were reexamined as the individual enantiome rs in the ex vivo assay, and the (S) enantiomer of 2,3-dihydro-6-(phen ylmethoxy)-3-benzofuranyl]urea, (+)-1a (SE 202235), was selected as th e compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its en antiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomer s of la. Enantioselective glucuronidation favoring (-)-1a was also fou nd in human liver microsomes.