Highly potent inhibitors of TNF-alpha production. Part II: metabolic stabilization of a newly found chemical lead and conformational analysis of an active diastereoisomer.
Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.
Matsui
Toshiaki
T
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Japan. to.matsui@ono.co.jp
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
Kamoshima
Wataru
W
Terai
Kouichiro
K
Ohno
Hiroyuki
H
Obata
Takaaki
T
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy; D004355:Drug Stability; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000494:pharmacology; D020714:Maximum Tolerated Dose; D051379:Mice; D008968:Molecular Conformation; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D007189:Indans; D008070:Lipopolysaccharides; D009943:Organophosphorus Compounds; D014409:Tumor Necrosis Factor-alpha