New bronchodilators. 3. Imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones.

Abstract

In order to develop new oral bronchodilators, a series of novel imidazol[4,5-c][1,8]naphthyridin-4(5H)-ones 5 were designed and synthesized. Some of these new heterocycles exhibited more potent bronchodilator activity in vitro and in vivo than theophylline. With respect to modification at the 5-position, both phenyl and n-butyl substitution produced potent activity. Though bulk tolerance at N-3 is observed with short and small lipophilic groups, any substitution at the other positions and transformations of the parent skeleton eliminated activity. Thus 5-phenyl-1H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (23) (KF17625), which satisfied these conditions, was selected for further studies (antigen inhalation-induced bronchospasm model; minimum effective dose (MED) = 1 mg/kg, po; antigen-induced contraction of trachea (the Schultz-Dale reaction), IC50 = 2.2 microM). Compound 23 inhibited carbachol-, histamine-, or leukotriene D4-induced contraction and relaxed spontaneous tone in guinea pig isolated tracheal preparations with, 4- to 16-fold greater potency than aminophylline. Thus it appeared to relax directly the airway smooth muscle. 23 did not have any influence on adenosine binding at 10 microM, but inhibited canine tracheal phosphodiesterase (PDE) IV (IC50 = 12 microM) and concanavalin-A-induced histamine release from rat mast cells (44% inhibition at 10 microM). Although the detailed mechanisms of these compounds remain to be elucidated, this series of novel tricyclic heterocycles represents a new class of bronchodilator.

• Authors: F Suzuki, T Kuroda, T Kawakita, H Manabe, S Kitamura, K Ohmori, M Ichimura, H Kase, S Ichikawa
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 35 Issue 26 Pg. 4866-74 (Dec 25 1992) ISSN: 0022-2623 [Print] United States
• PMID: 1479586 (Publication Type: Journal Article)

Chemical References

• Bronchodilator Agents
• Imidazoles
• Naphthyridines
• Phosphodiesterase Inhibitors
• KF 17625

Topics

• Animals
• Bronchodilator Agents (chemical synthesis, chemistry, pharmacology)
• Drug Interactions
• Guinea Pigs
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Male
• Mice
• Muscle Relaxation (drug effects)
• Muscle, Smooth (drug effects)
• Naphthyridines (chemical synthesis, chemistry, pharmacology)
• Phosphodiesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Trachea (drug effects)