Novel potent and selective Ca2+ release-activated Ca2+ (CRAC) channel inhibitors. Part 3: synthesis and CRAC channel inhibitory activity of 4'-[(trifluoromethyl)pyrazol-1-yl]carboxanilides.
From a series of 4'-[(trifluoromethyl)pyrazol-1-yl]carboxanilides derived from 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide, one inhibited thapsigargin-induced Ca2+ influx in Jurkat T cells (IC(50)=77 nM) and exhibited high selectivity for the CRAC channel over the VOC channel (index: >130). Another acted as an inhibitor for both T lymphocyte activation-induced diseases and ovalbumin-induced airway eosinophilia in rats (ED(50)=1.3 mg/kg) p.o.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yasuhiro.yonetoku@jp.astellas.com
Yasuhiro
Y
Yonetoku
Hirokazu
H
Kubota
Yoji
Y
Miyazaki
Yoshinori
Y
Okamoto
Masashi
M
Funatsu
Noriko
N
Yoshimura-Ishikawa
Jun
J
Ishikawa
Taiji
T
Yoshino
Makoto
M
Takeuchi
Mitsuaki
M
Ohta
D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D000813:Anilides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011720:Pyrazoles; D019284:Thapsigargin; D002118:Calcium