Identification of a novel series of potent and selective CCR6 inhibitors as biological probes |
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Authors: | Taisuke Tawaraishi Nobuki Sakauchi Kousuke Hidaka Kyoko Yoshikawa Toshitake Okui Haruhiko Kuno Ikumi Chisaki Kazuyoshi Aso |
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Institution: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan;2. Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan |
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Abstract: | CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6. |
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Keywords: | CCR6 Biological probe Autoimmune diseases Non-autoimmune diseases Cell migration Gi signal ERK phosphorylation Corresponding author |
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