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

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

doi:10.1021/acsmedchemlett.5b00253

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

ACS Med Chem Lett. 2015 Nov 4;7(1):23-7. doi: 10.1021/acsmedchemlett.5b00253. eCollection 2016 Jan 14.

Authors

Kazuyuki Hirata¹, Masayuki Kotoku¹, Noriyoshi Seki¹, Takaki Maeba¹, Katsuya Maeda¹, Shintaro Hirashima¹, Takayuki Sakai¹, Shingo Obika¹, Akimi Hori¹, Yasunori Hase¹, Takayuki Yamaguchi¹, Yoshiaki Katsuda¹, Takahiro Hata¹, Naoki Miyagawa¹, Kojo Arita¹, Yukihiro Nomura¹, Kota Asahina¹, Yusuke Aratsu¹, Masafumi Kamada², Tsuyoshi Adachi², Masato Noguchi², Satoki Doi², Paul Crowe³, Erin Bradley³, Ruo Steensma³, Haiyan Tao³, Morgan Fenn³, Robert Babine³, Xiaolin Li³, Scott Thacher³, Hiromasa Hashimoto¹, Makoto Shiozaki¹

Affiliations

¹ Chemical Research Laboratories, Biological Pharmacological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
² Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
³ Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.

Abstract

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.

Keywords: RORγ; Th17; fraction of sp3 carbon atoms (Fsp3); immunological diseases; ligand efficiency (LE); nuclear receptor.