Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 1: synthesis and inhibitory activity of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides.
We synthesized and evaluated a series of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides to identify potent inhibitors of calcium-release-activated calcium (CRAC) channels with greater selectivity than voltage-operated calcium (VOC) channels. These efforts resulted in identification of compounds 22 and 24. The former exhibits highly potent and selective CRAC channel inhibitory activity, and the latter inhibited phytohemagglutinin-induced interleukin-2 production by Jurkat T lymphocytes and concanavalin A-induced hepatitis in mice.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yasuhiro.yonetoku@jp.astellas.com
Yasuhiro
Y
Yonetoku
Hirokazu
H
Kubota
Yoshinori
Y
Okamoto
Akira
A
Toyoshima
Masashi
M
Funatsu
Jun
J
Ishikawa
Makoto
M
Takeuchi
Mitsuaki
M
Ohta
Shin-ichi
S
Tsukamoto
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016716:PC12 Cells; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007376:Interleukin-2; D013876:Thiophenes