Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents:  Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

• Published in: Journal of medicinal chemistry Vol. 42; no. 6; pp. 1088 - 1099
• Main Authors: Ukita, Tatsuzo, Sugahara, Masakatsu, Terakawa, Yoshihiro, Kuroda, Tooru, Wada, Kazuteru, Nakata, Aya, Ohmachi, Yasushi, Kikkawa, Hideo, Ikezawa, Katsuo, Naito, Kazuaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.03.1999; Amer Chemical Soc
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animals; Anti-Asthmatic Agents - chemical synthesis; Anti-Asthmatic Agents - chemistry; Anti-Asthmatic Agents - pharmacology; Anti-Asthmatic Agents - toxicity; Binding, Competitive; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Bronchoconstriction - drug effects; Chemistry, Medicinal; Cyclic Nucleotide Phosphodiesterases, Type 4; Dogs; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Ferrets; Guinea Pigs; Heart Rate - drug effects; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Phthalazines - toxicity; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - toxicity; Respiratory system; Science & Technology; Structure-Activity Relationship; Vomiting - chemically induced; DESIGN; MULTIPLE MOLECULAR-FORMS; ANALOGS; MUSCLE; ASTHMA; LIGNANS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; IV; ROLIPRAM; Intravenous administration; Nitrogen heterocycle; Esterases; Phosphoric diester hydrolases; Antiasthma agent; Pyridine derivatives; Antispasmodic agent; Hydrochlorides; Bicyclic compound; Aromatic compound; Chemical synthesis; Dog; Fissipedia; Carnivora; Diol; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Oral administration; Enzyme inhibitor; Naphthalene derivatives; Biological activity; Phthalazine derivatives; Vertebrata; Mammalia; Cyclization; Animal; Ferret; Hydrolases
• DOI: 10.1021/jm980314l
• ISSN: 0022-2623

The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585·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-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous 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; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited 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 broad margin between the K i value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).