New antiinflammatory agents. 2. 5-Phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones: a new class of nonsteroidal antiinflammatory agents with potent activity like glucocorticoids.
We previously described new antiinflammatory agents, 4-hydroxy-2-oxo-1-phenyl-1H-1,8-naphthyridine-3-carboxamides 1. Further modification of the compounds bearing 1-phenyl-1,8-naphthyridin-2-one as a mother skeleton led to 5-phenylimidazo[4,5-c][1,8]naphthyridin-4(5H)-one derivatives 2 and 3. Regioselective synthesis of these compounds bearing a substituent at the 1- or 3-position was conducted according to the method shown in Schemes I and II. In this series of compounds, antiinflammatory activities were greatly influenced by the position and nature of substituents on imidazole. 3-Alkyl or 3-benzyl substitution result in the potent activity, but 1-substitution did not. Minor modification of the benzyl group reduced or eliminated the activity. Detailed examination of structure-activity relationships led to 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (22), which exhibited potent oral antiinflammatory activities in carrageenan-, zymosan-, and reversed passive Arthus reaction-induced rat paw edemas (ED40 = 5.3, 0.37 mg/kg, ED50 = 0.47 mg/kg, respectively). This broad activity of 22 was like that of glucocorticoids. Compound 22 did not affect activities of CO and 5-LO enzymes and receptor binding of various ligands. As one of the mechanisms of action, induction of release of glucocorticoids was postulated. These results suggest that 22 represents a novel class of antiinflammatory agents.
Suzuki
F
F
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., Shizuoka, Japan.
Kuroda
T
T
Tamura
T
T
Sato
S
S
Ohmori
K
K
Ichikawa
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D009287:Naphthyridines