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

ACS Medicinal Chemistry Letters 2026 Open access

Read full text
Authors: Michael D. Mandler, Yeheng Zhu, Emily C. Hollenbeck, Milinda Ziegler, Shana Posy, Shilpaa Mukundan, O. Scott Halpern, James P. Driscoll, Tao Wang, Li Huang, Gayani Fernando, Helen Jung
+11 more Ling Li, Jingfang Cutrone, Dnyaneshwar Baswar, Prasanth Eapen, Sarah C. Traeger, Shivangi Srivastava, Jonathan B. Olsen, Gerry G. Everlof, Glenda Trujillo, Bruce A. Ellsworth, Alicia Regueiro‐Ren
DOI: 10.1021/acsmedchemlett.5c00760
Cited by: 0
References: 41

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.

Fields of Study & Subjects

Immune Response and Inflammation Synthesis and Characterization of Heterocyclic Compounds Immunotoxicology and immune responses

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Volume
17
Issue
3
Pages
727–732
Publication date
27 February 2026
Language
EN