Abstract

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo;c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC₅₀ of 1 μM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID₅₀ values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 ± 0.19, 1.65 ± 0.29 and 0.93 ± 0.24 μg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID₅₀ = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activityin vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D₄ (LTD₄) [ID₅₀ = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD₄ challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD₄ challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD₄ challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnette et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.