2. Academic Validation
  3. Discovery of Triazine-Based Toll-Like Receptor 9 Antagonists with Oral Activity

Discovery of Triazine-Based Toll-Like Receptor 9 Antagonists with Oral Activity

  • ACS Med Chem Lett. 2026 Feb 27;17(3):727-732. doi: 10.1021/acsmedchemlett.5c00760.
Michael D Mandler 1,  Yeheng Zhu 1,  Emily C Hollenbeck 2,  Milinda Ziegler 1,  Shana L Posy 1,  Shilpaa Mukundan 1,  O Scott Halpern 1,  James P Driscoll 2,  Tao Wang 1,  Li Huang 1,  Gayani Fernando 1,  Helen Jung 1,  Ling Li 1,  Jingfang Cutrone 1,  Dnyaneshwar Baswar 3,  Prasanth Eapen 3,  Sarah C Traeger 1,  Shivangi Srivastava 1,  Jonathan Olsen 1,  Gerry G Everlof 1,  Glenda Trujillo 1,  Bruce A Ellsworth 1,  Alicia Regueiro-Ren 1
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Research, Princeton, New Jersey 08543, United States.
  • 2 Bristol Myers Squibb Research, Brisbane, California 94005, United States.
  • 3 Biocon Bristol Myers Squibb R&D Centre, Bangalore 560100, India.
PMID: 41847634 DOI: 10.1021/acsmedchemlett.5c00760
Abstract

A screen for small-molecule antagonists of Toll-like Receptor 9 (TLR9) uncovered a triazine chemotype hit with potential liabilities, including a nitroarene, a hydrazone, and a free phenol. Systematic replacement of these liabilities led to the identification of compound 20, which maintained submicromolar TLR9 antagonism while exhibiting oral bioavailability and robust pharmacodynamic effects in a bleomycin-induced lung fibrosis model.

Keywords

Toll-like receptor 9; bleomycin-induced lung fibrosis model; idiopathic pulmonary fibrosis.

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