Highly potent inhibitors of TNF-alpha production. Part 2: identification of drug candidates.
Metabolic stabilization of the chemical lead 1, which is a structurally novel inhibitor of TNF-alpha production, was accomplished by introducing a (1S)-methyl group into the optically active backbone. As a result, 2, 3 and 4 were identified as drug candidates and evaluated pharmacologically. The analysis of an active conformer was also carried out.
Matsui
Toshiaki
T
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, 913-8638, Fukui, Japan
Kondo
Takashi
T
Nishita
Yoshitaka
Y
Itadani
Satoshi
S
Tsuruta
Hiroshi
H
Fujita
Setsuko
S
Omawari
Nagashige
N
Sakai
Masaru
M
Nakazawa
Shuichi
S
Ogata
Akihito
A
Mori
Hideaki
H
Ohno
Hiroyuki
H
Obata
Takaaki
T
Nakai
Hisao
H
Toda
Masaaki
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001596:Benzylamines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha