Discovery of Triazine-Based Toll-Like Receptor 9 Antagonists with Oral Activity
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 <b>20</b>, which maintained submicromolar TLR9 antagonism while exhibiting oral bioavailability and robust pharmacodynamic effects in a bleomycin-induced lung fibrosis model.
Authors
- Michael D. Mandler (ORCID: https://orcid.org/0000-0003-4681-7473)
- Yeheng Zhu
- Jingfang Cutrone
- Alicia Regueiro‐Ren (ORCID: https://orcid.org/0000-0003-2991-719X)
- James P. Driscoll (ORCID: https://orcid.org/0000-0002-3736-1673)
- Dnyaneshwar Baswar
- Bruce A. Ellsworth (ORCID: https://orcid.org/0000-0002-2788-1819)
- Shana Posy (ORCID: https://orcid.org/0000-0001-9298-899X)
- Shilpaa Mukundan
- Glenda Trujillo (ORCID: https://orcid.org/0000-0002-6061-5264)
- Sarah C. Traeger
- Gerry Everlof
- Jonathan B. Olsen
- Huang Li (ORCID: https://orcid.org/0000-0003-2877-3526)
- Tao Wang
- Emily C. Hollenbeck
- O. Scott Halpern
- Gayani Fernando
- Milinda Ziegler
- Shivangi Srivastava
- Prasanth Eapen
- Helen Jung
- Ling Li
Institutions
- Bristol-Myers Squibb (Germany) (DE)
- Biocon (Switzerland) (CH)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2026-02-27
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00760
- Primary Topic
- Synthesis and Characterization of Heterocyclic Compounds
- Type
- article
- Field-Weighted Citation Impact
- 0.00