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
  • 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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