Synthesis and pharmacological properties of N-[4-[4-(1H-indol-3-yl) piperidinoalkyl]-2-thiazolyl]alkanesulfonamides as novel antiallergic agents.
A number of N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2- thiazolyl]alkanesulfonamides (8--21) were synthesized and evaluated for their preventive effects on systemic anaphylaxis in guinea pigs. Structure-activity analysis revealed that methane- and ethanesulfonamide derivatives having a one to three methylene tether between the piperidine and thiazole rings exhibited potent activity but the introduction of a substituent on the indole part reduced the activity. Administration (100 mg/kg p.o.) of the four compounds 8, 9, 12, 13, together with ketotifen, oxatomide, terfenadine and azelastine as reference compounds, to mice revealed that only compound 8 caused no significant increase of the sleeping time induced by hexobarbital. In addition, compound 8 (10 mg/kg i.v.) did not change the electroencephalogram in conscious rabbits. These results led to the selection of N-[4-[4-(1H-indol-3-yl)piperidinomethyl]-2-thiazolyl]methanesulfon amide (8, FK613) for further development as a novel antiallergic agent. Clinical evaluation of FK613 is now in progress.
Shigenaga
S
S
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Manabe
T
T
Matsuda
H
H
Fujii
T
T
Hiroi
J
J
Matsuo
M
M
D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010047:Ovalbumin / Q000276:immunology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D007211:Indoles; D013449:Sulfonamides; D013844:Thiazoles; D010047:Ovalbumin