We evaluated the airway activity of the novel
phosphodiesterase type 4 inhibitor SB 207499 [
Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-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 microM 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 microg/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 activity in 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 (Barnett et al., 1998), suggest that
SB 207499 will be useful in the treatment of
asthma and other inflammatory disorders.