GS-9688（Selgantolimod）作为有效的选择性口服Toll样受体8激动剂

StephenW

J Med Chem. 2020 May 14. doi: 10.1021/acs.jmedchem.0c00100. [Epub ahead of print]
Discovery of GS-9688 (Selgantolimod), as a Potent and Selective Oral Toll-like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B.
Mackman RL, Mish M, Chin G, Perry J, Appleby TC, Aktoudianakis V, Metobo S, Pyun P, Niu C, Daffis S, Yu H, Zheng J, Villaseñor AG, Zablocki J, Chamberlain J, Jin H, Lee G, Suekawa-Pirrone K, Santos R, Delaney WE, Fletcher S.
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.

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

StephenW

J Med化学2020年5月14日。doi：10.1021 / acs.jmedchem.0c00100。 [Epub提前发布]
GS-9688（Selgantolimod）作为有效的选择性口服Toll样受体8激动剂的发现，用于治疗慢性乙型肝炎。
Mackman RL，Mish M，Chin G，Perry J，Appleby TC，Aktoudianakis V，Metobo S，Pyun P，Nu C，Daffis S，Yu H，Zheng J，VillaseñorAG，Zablocki J，Chamberlain J，Jin H，Lee G ，Suekawa-Pirrone K，Santos R，Delaney WE，Fletcher S.
抽象

Toll样受体8（TLR8）识别病原体衍生的单链RNA片段，以触发先天性和适应性免疫反应。慢性乙型肝炎（CHB）与机能障碍的免疫反应有关，因此选择性TLR8激动剂可能是一种有效的治疗选择。基于结构的双TLR7 / 8激动剂的优化导致选择性TLR8临床候选物的鉴定（R）-2-（（2-氨基-7-氟吡啶并[3,2-d]嘧啶-4-基）氨基） -2-甲基己-1-醇（GS-9688，（R）-7）。在人外周血单核细胞（PBMC）中观察到强效的TLR8激动作用（IL-12p40 EC50 = 220 nM）和> 100倍的TLR7选择性（IFN-αEC50> 50 µM）。 TLR8-胞外域：（R）-7复合物证实了TLR8的结合以及与TLR8残基Asp545的直接配体相互作用。口服（R）-7在临床前物种中具有良好的吸收和较高的首过清除率。在用（R）-7刺激的PBMC培养基中处理的HBV感染的原代人肝细胞中观察到病毒标志物减少，支持（R）-7用于CHB治疗的临床发展。

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