Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4)inhibitor SB 207499 (Ariflo) in the guinea pig

We evaluated the airway activity of the novel phosphodiesterase type 4 inhi bitor SE 207499 [Arifio; c-4-cyano-4-(3-cyclopentytoxy-4-methoxyphenyl-r-1 -cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced c ontractions of guinea pig isolated tracheal strips were inhibited by SE 207 499 with an EC50 of 1 mu M but had little or no effect on exogenous agonist -induced contraction, which suggests that its effect on OA-induced contract ion in vitro is primarily due to inhibition of mediator release from mast c ells. In anesthetized guinea pigs, SE 207499 inhibited OA-induced bronchoco nstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively . At 1,3 and 6 hr after SE 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 mu g/ml, respectively, of SE 207499. SE 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 activity in vitro, SE 207499 inhibi ted bronchospasm induced by i.v. leukotriene D-4 (LTD,) [ID,, = 3 mg/kg i.v .]. The bronchorelaxant effect of i.v.-administered SE 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced ai rway tone, but it did not alter base line or enhance salbutamol-induced car diovascular effects. In conscious guinea pigs, SE 207499 (10 or 30 mg/kg p. o.), 1 hr before antigen or LTD, challenge, markedly reduced bronchospasm a nd subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SE 207499 administered after OA or LTD, challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr a fter LTD, challenge. These results, coupled with the broad anti-inflammator y activity of SE 207499 previously described (Barnette et al., 1998), sugge st that SE 207499 will be useful in the treatment of asthma and other infla mmatory disorders.