Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B

J Med Chem. 2020 Sep 24;63(18):10188-10203. doi: 10.1021/acs.jmedchem.0c00100.

Richard L Mackman ¹, Michael Mish ¹, Gregory Chin ¹, Jason K Perry ¹, Todd Appleby ¹, Vangelis Aktoudianakis ¹, Sammy Metobo ¹, Peter Pyun ¹, Congrong Niu ¹, Stephane Daffis ¹, Helen Yu ¹, Jim Zheng ¹, Armando G Villasenor ¹, Jeff Zablocki ¹, Jason Chamberlain ¹, Haolun Jin ¹, Gary Lee ¹, Kimberley Suekawa-Pirrone ¹, Rex Santos ¹, William E Delaney 4th ¹, Simon P Fletcher ¹

Affiliations

Affiliation

1 Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.

PMID: 32407112 DOI: 10.1021/acs.jmedchem.0c00100

Abstract

Toll-like Receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 Agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, (R)-7). Potent TLR8 agonism (IL-12p40 EC₅₀ = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC₅₀ > 50 μM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with (R)-7, supporting the clinical development of (R)-7 for the treatment of CHB.

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