title: SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor.
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.
authors.affiliation: 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.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hirata
authors.affiliation: 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.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kotoku
authors.affiliation: 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.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Seki
authors.affiliation: 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.
authors.forename: Takaki
authors.initials: T
authors.lastname: Maeba
authors.affiliation: 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.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: 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.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hirashima
authors.affiliation: 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.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakai
authors.affiliation: 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.
authors.forename: Shingo
authors.initials: S
authors.lastname: Obika
authors.affiliation: 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.
authors.forename: Akimi
authors.initials: A
authors.lastname: Hori
authors.affiliation: 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.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hase
authors.affiliation: 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.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: 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.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katsuda
authors.affiliation: 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.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hata
authors.affiliation: 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyagawa
authors.affiliation: 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.
authors.forename: Kojo
authors.initials: K
authors.lastname: Arita
authors.affiliation: 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.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: 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.
authors.forename: Kota
authors.initials: K
authors.lastname: Asahina
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Aratsu
authors.affiliation: Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kamada
authors.affiliation: Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Doi
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Crowe
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Bradley
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Ruo
authors.initials: R
authors.lastname: Steensma
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tao
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Morgan
authors.initials: M
authors.lastname: Fenn
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Babine
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.affiliation: Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Thacher
authors.affiliation: 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.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiozaki
keywords: RORγ; Th17; fraction of sp3 carbon atoms (Fsp3); immunological diseases; ligand efficiency (LE); nuclear receptor
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