Structure-Based Design of 2-(Pyridone)Indoles as Antagonists of the Toll-Like Receptors TLR7 and TLR8 for the Treatment of Autoimmune Disorders
Dharmpal S. Dodd, John L. Gilmore, Tasir S. Haque, Brian K. Whiteley, Shana L. Posy, Dawn Mulligan, David Critton, Rosemary Zhang, Hongchen Qiu, Mary Ellen Cvijic, Murali Subramanian, Debarati Mazumder Tagore, Shailesh Dudhgaonkar, Mary Harner, Louis J. Lombardo, John E. Macor, Stefan Ruepp, Gary L. Schieven, Alaric J. DyckmanAbstract
Toll-like receptors 7 and 8 (TLR7/8) are innate immune sensors whose activation by endogenous RNA ligands is a hallmark of chronic autoimmune disorders, notably cutaneous and systemic lupus. We present the structure-based design and optimization of 2-(pyridin-2(1H)-one)indoles as potent dual TLR7/8 antagonists with properties improved over our prior series, including increased permeability, reduced ion channel activity, and reduced volume of distribution at steady state (Vss). Initial pyridone leads displayed unexpected anti-proliferative activity in a panel of immune cell lines; optimization against an identified off-target BRD4 liability, hypothesized to drive this effect, delivered potent antagonists devoid of BRD4 binding and of anti-proliferative activity. These compounds potently inhibited TLR7/8-mediated IL-6 production in human whole blood, with 9a giving IC50 values of 9.4 and 1.3 nM against TLR7 and TLR8, respectively. This orally bioavailable lead dose-dependently suppressed TLR7-mediated IL-6 and IFNα release in a mouse pharmacodynamic model.