Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: Synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives

The structural requirements for potent and selective PDE4 inhibition were r evealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-258 5 . HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-ind uced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction o f histamine-induced bronchoconstriction, intraduodenally) in guinea pigs wi th little cardiovascular effects. Furthermore, 3kg induced significantly we aker emetic effects than RP73401 after oral administration in ferrets and i ntravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at; a dose of 0.3 mg/kg, iv; RP 73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomi ted at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0.85 nM ). This may imply that 3kg has an improved therapeutic ratio because of a b road margin between the K-i value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).