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Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-14 , 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 1 , Simon P Fletcher 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-14 , 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 1 , Simon P Fletcher 1
Affiliation
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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.
中文翻译：
GS-9688（Selgantolimod）作为有效的和选择性的口服Toll受体8激动剂的发现，用于治疗慢性乙型肝炎。
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。对双TLR7 / 8激动剂的基于结构的优化导致对选择性TLR8临床候选物（R）-2-（（2-氨基-7-氟吡啶并[3,2 - d ]嘧啶-4-基）氨基的鉴定）-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TLR8激动作用（IL-12p40 EC 50 = 220 nM）和> 100倍TLR7选择性（IFN- αEC 50 > 50μM）。TLR8外部域：(R）-7复合物证实了TLR8结合以及与TLR8残基Asp545的直接配体相互作用。在临床前物种中，口服（R）-7具有良好的吸收性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的减少，支持（R）-7治疗CHB的临床发展。
更新日期：2020-05-14
中文翻译：
GS-9688（Selgantolimod）作为有效的和选择性的口服Toll受体8激动剂的发现，用于治疗慢性乙型肝炎。
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。对双TLR7 / 8激动剂的基于结构的优化导致对选择性TLR8临床候选物（R）-2-（（2-氨基-7-氟吡啶并[3,2 - d ]嘧啶-4-基）氨基的鉴定）-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TLR8激动作用（IL-12p40 EC 50 = 220 nM）和> 100倍TLR7选择性（IFN- αEC 50 > 50μM）。TLR8外部域：(R）-7复合物证实了TLR8结合以及与TLR8残基Asp545的直接配体相互作用。在临床前物种中，口服（R）-7具有良好的吸收性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的减少，支持（R）-7治疗CHB的临床发展。
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