Symmetrical bis(heteroarylmethoxyphenyl) alkylcarboxylic acids as inhibitors of leukotriene biosynthesis

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigat ed as inhibitors of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmetho xy)phenyl)pent acid sodium salt (47.Na) met our design parameters for a dru g candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutroph ils, 47.Na inhibited ionophore-stimulated LTB4 formation with an IC50 = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC4 and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC4 (IC50 = 0.16 nM) over PGE(2) (IC50 = 1500 nM). Preliminary pharmacokinetic evalu ation in rat and cynomolgus monkey demonstrated good oral bioavailability a nd elimination half-lives of 9 and 5 h, respectively. Pharmacological evalu ation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED50 = 3 mg/kg) and a rat peritoneal passive an aphylaxis model (LTB4, ED50 = 2.5 mg/kg; LTE4, ED50 = 1.0 mg/kg). In a mode l of airway constriction induced by antigen challenge in actively sensitize d guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED50 = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at t he stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathw ays leading to LTB4 and LTC4 but not PGH(2) biosynthesis. However, 47.Na do es not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; ther efore it is likely that 47.Na acts as a FLAP inhibitor.