Structure-Based Design of 2-(Pyridone)Indoles as Antagonists of the Toll-Like Receptors TLR7 and TLR8 for the Treatment of Autoimmune Disorders

Abstract 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.