N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (
SCH 351591) has been identified as a potent (IC(50) = 58 nM) and highly selective type 4
phosphodiesterase (
PDE4) inhibitor with oral bioactivity in several animal models of
lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective
PDE4 inhibitor (IC(50) = 20 nM). Both
SCH 351591 and SCH 365351 inhibited
cytokine production in human blood mononuclear cell preparations. Oral
SCH 351591 significantly attenuated
allergen-induced
eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When
SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suum-induced lung
eosinophilia was blocked.
Hyperventilation-induced
bronchospasm in nonallergic guinea pigs, a model for
exercise-induced asthma, was also suppressed significantly by oral
SCH 351591 at 0.3 mg/kg.
Cilomilast (
SB 207499;
Ariflo), a
PDE4 inhibitor currently being developed for
asthma and
chronic obstructive pulmonary disease (
COPD), was 10- to 30-fold less potent than
SCH 351591 at inhibiting guinea pig lung
eosinophilia and
hyperventilation-induced
bronchospasm. In a ferret model of
emesis, maximum nonemetic oral doses of
SCH 351591 and
cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting
hyperventilation-induced
bronchospasm in guinea pigs gave a therapeutic ratio of 16 for
SCH 351591 and 4 for
cilomilast. Thus,
SCH 351591 exhibits a promising preclinical profile as a treatment for
asthma and
COPD.