Novel antiallergic and antiinflammatory agents. Part II: Synthesis and pharmacology of TYB-2285 and its related compounds.
A series of m-bis(glycoloylamino)benzene derivatives was synthesized by treatment of the corresponding m-diaminobenzene derivatives with glycoloyl chloride derivatives in pyridine. Hydrolysis of acetyl compounds gave hydroxy derivatives, from which other acyl derivatives could be synthesized. These compounds were tested in the rat PCA (passive cutaneous anaphylaxis) assay by oral administration. Benzonitrile derivatives (4c, 5c, 6c, 4h, 5h) exhibited notable inhibition in this assay. Compounds 5c and 6c also showed remarkable inhibition of eosinophil adhesion to TNF- (tumor necrosis factor) alpha-treated HUVEC (human umbilical vein endothelial cells) in the range of 10(-8)-10(-5) M. Compound 5c is now under investigation in Japan as TYB-2285 (Figure 1) for asthma and atopic dermatitis in phase II clinical studies.
Ban
M
M
Pharmaceuticals Research Center, TOYOBO Co., Ltd, Ohtsu, Shiga, Japan.
Taguchi
H
H
Katsushima
T
T
Takahashi
M
M
Shinoda
K
K
Watanabe
A
A
Tominaga
T
T
D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004804:Eosinophils / Q000502:physiology; D006801:Humans; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; C081050:3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile