SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

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• 作者：Kazuyuki Hirata ; Masayuki Kotoku ; Noriyoshi Seki ; Takaki Maeba ; Katsuya Maeda ; Shintaro Hirashima ; Takayuki Sakai ; Shingo Obika ; Akimi Hori ; Yasunori Hase ; Takayuki Yamaguchi ; Yoshiaki Katsuda ; Takahiro Hata ; Naoki Miyagawa ; Kojo Arita ; Yukihiro Nomura ; Kota Asahina ; Yusuke Aratsu ; Masafumi Kamada ; Tsuyoshi Adachi ; Masato Noguchi ; Satoki Doi ; Paul Crowe ; Erin Bradley ; Ruo Steensma ; Haiyan Tao ; Morgan Fenn ; Robert Babine ; Xiaolin Li ; Scott Thacher ; Hiromasa Hashimoto ; Makoto Shiozaki
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：7
• 期：1
• 页码：23-27
• 全文大小：346K
• ISSN：1948-5875

文摘

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 sp³ carbon atoms (Fsp³), 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.