Synthetic Studies on Selective Type 4 Phosphodiesterase (PDE 4) Inhibitors. 1. Structure–Activity Relationships and Pharmacological Evaluation of 1,8-Naphthyridin-2(1H)-one Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 50; no. 8; pp. 1050 - 1059
• Main Authors: Takayama, Kazuhisa, Iwata, Masahiro, Hisamichi, Hiroyuki, Okamoto, Yoshinori, Aoki, Motonori, Niwa, Akira
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.08.2002; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 1,8-naphthyridin-2(1H)-one; 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; Biological and medical sciences; Carrageenan - administration & dosage; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Evaluation, Preclinical - methods; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Naphthyridines - chemistry; Naphthyridines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; phosphodiesterase 4 inhibitor; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Physical Sciences; Pleurisy - chemically induced; Pleurisy - enzymology; Rats; Respiratory system; rolipram; Science & Technology; Structure-Activity Relationship; YM-10335; phosphodiesterase 4 inhibitor; rolipram; DESIGN; 1,8-naphthyridin-2(1H)-one; YM-10335; EOSINOPHIL; Rat; Nitrogen heterocycle; Isozyme; Leukocyte; Lactam; Esterases; Selectivity; Phosphoric diester hydrolases; Antiasthma agent; Structure activity relation; Pleurisy; Bicyclic compound; Inhibition; Chemical synthesis; Tumor necrosis factor α; Human; 3',5'-Cyclic-nucleotide phosphodiesterase; Respiratory disease; Enzyme; Rodentia; Antiinflammatory agent; Benzene derivatives; Cytokine; Oral administration; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Hydrolases; Pleural disease
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.50.1050

In order to develop novel and orally active phosphodiesterase (PDE) 4 inhibitors, random screening was performed using our chemical library to find YM-10335 possessing the 1,8-naphthyridin-2(1H)-one skeleton which is a completely different structure from rolipram. In this report, the syntheses and structure–activity relationships of the YM-10335 derivatives were described. Some compounds showed selective inhibitory activities for PDE 4 derived from human peripheral blood cells and no effect on the other PDE types (1, 2, 3, 5). The inhibition of the tumor necrosis factor-alpha (TNF-α) release in vitro and the carrageenan-induced pleurisy in rats were also described.