Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold

  • J Med Chem. 2019 Mar 14;62(5):2837-2842. doi: 10.1021/acs.jmedchem.8b01567.
Masayuki Kotoku  1 ,  Takaki Maeba ,  Shingo Fujioka ,  Masahiro Yokota ,  Noriyoshi Seki ,  Keisuke Ito ,  Yoshihiro Suwa ,  Taku Ikenogami ,  Kazuyuki Hirata ,  Yasunori Hase ,  Yoshiaki Katsuda ,  Naoki Miyagawa ,  Kojo Arita ,  Kota Asahina ,  Masato Noguchi ,  Akihiro Nomura ,  Satoki Doi ,  Tsuyoshi Adachi ,  Paul Crowe  2 ,  Haiyan Tao  2 ,  Scott Thacher  2 ,  Hiromasa Hashimoto ,  Takayoshi Suzuki  1 ,  Makoto Shiozaki
Affiliations
  • 1. Graduate School of Medical Science , Kyoto Prefectural University of Medicine , 1-5 Shimogamo-hangi-cho , Sakyo-ku , Kyoto 603-0823 , Japan.
  • 2. Orphagen Pharmaceuticals , 11558 Sorrento Valley Road, Suite 4 , San Diego , California 92121 , United States.
PMID: 30776227 DOI: 10.1021/acs.jmedchem.8b01567
Abstract

Starting from a previously reported RORγ Inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ Inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

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