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

ABSTRACT: A novel series of ROR? 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 ROR? inhibitor 3z.

SUBMITTER: Hirata K

PROVIDER: S-EPMC4716592 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Hirata Kazuyuki K Kotoku Masayuki M Seki Noriyoshi N Maeba Takaki T Maeda Katsuya K Hirashima Shintaro S Sakai Takayuki T Obika Shingo S Hori Akimi A Hase Yasunori Y Yamaguchi Takayuki T Katsuda Yoshiaki Y Hata Takahiro T Miyagawa Naoki N Arita Kojo K Nomura Yukihiro Y Asahina Kota K Aratsu Yusuke Y Kamada Masafumi M Adachi Tsuyoshi T Noguchi Masato M Doi Satoki S Crowe Paul P Bradley Erin E Steensma Ruo R Tao Haiyan H Fenn Morgan M Babine Robert R Li Xiaolin X Thacher Scott S Hashimoto Hiromasa H Shiozaki Makoto M

ACS medicinal chemistry letters 20151104 1

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. ...[more]

PMID: 26819660

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