Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

Autor:	Maeba T; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.; Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan., Hirata K; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Kotoku M; Akros Pharma Inc., Boston Office, One Broadway, 14th Floor, Cambridge, Massachusetts 02142, United States., Seki N; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Maeda K; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Hirashima S; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Yamanaka H; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Sakai T; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Obika S; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Hori A; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Hara Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Noji S; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Suwa Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Yokota M; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Fujioka S; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Yamaguchi T; Pharmaceutical Division, Japan Tobacco Inc., 3-4-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan., Katsuda Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Hata T; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Miyagawa N; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Arita K; Pharmaceutical Division, Japan Tobacco Inc., 3-4-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan., Nomura Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Taniguchi T; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Asahina K; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Aratsu Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Naka Y; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Adachi T; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Nomura A; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Akai S; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Oshida SI; Central Pharmaceutical Research Institute, Yokohama Research Center, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan., Pai S; Akros Pharma Inc., 302 Carnegie Center, Suite 300, Princeton, New Jersey 08540, United States., Crowe P; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Bradley E; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Steensma R; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Tao H; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Fenn M; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Babine R; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Li X; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Thacher S; Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States., Soeta T; Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan., Ukaji Y; Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan., Shiozaki M; Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jan 25; Vol. 67 (2), pp. 952-970. Date of Electronic Publication: 2024 Jan 03.
DOI:	10.1021/acs.jmedchem.3c01933
Abstrakt:	A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.
Databáze:	MEDLINE
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