SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduc...

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Published in:ACS medicinal chemistry letters 2016-01, Vol.7 (1), p.23-27
Main Authors: Hirata, Kazuyuki, Kotoku, Masayuki, Seki, Noriyoshi, Maeba, Takaki, Maeda, Katsuya, Hirashima, Shintaro, Sakai, Takayuki, Obika, Shingo, Hori, Akimi, Hase, Yasunori, Yamaguchi, Takayuki, Katsuda, Yoshiaki, Hata, Takahiro, Miyagawa, Naoki, Arita, Kojo, Nomura, Yukihiro, Asahina, Kota, Aratsu, Yusuke, Kamada, Masafumi, Adachi, Tsuyoshi, Noguchi, Masato, Doi, Satoki, Crowe, Paul, Bradley, Erin, Steensma, Ruo, Tao, Haiyan, Fenn, Morgan, Babine, Robert, Li, Xiaolin, Thacher, Scott, Hashimoto, Hiromasa, Shiozaki, Makoto
Format: Article
Language:English
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Summary:A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00253