吡咯并[3,2-d]嘧啶Toll样受体7（TLR7）选择性激动剂治疗乙型肝

StephenW

J Med Chem. 2017 Jul 3. doi: 10.1021/acs.jmedchem.7b00365. [Epub ahead of print]
Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B.
McGowan DC, Herschke F, Pauwels F, Stoops B, Smyej I, Last S, Pieters S, Embrechts W, Khamlichi MD, Thoné T, Van Schoubroeck B, Mostmans W, Wuyts D, Verstappen D, Scholliers A, De Pooter D, Dhuyvetter D, Borghys H, Tuefferd M, Arnoult E, Hong J, Fanning G, Bollekens J, Urmaliya V, Teisman A, Horton H, Jonckers THM, Raboisson PJMB.
Abstract

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.

PMID:
    28671847
DOI:
    10.1021/acs.jmedchem.7b00365

J Med Chem。 2017年7月3. doi：10.1021 / acs.jmedchem.7b00365。 [提前印刷]
吡咯并[3,2-d]嘧啶Toll样受体7（TLR7）选择性激动剂治疗乙型肝炎的鉴定与优化
McGowan DC，Herschke F，Pauwels F，Stoops B，Smyej I，Last S，Pieters S，Embrechts W，Khamlichi MD，ThonéT，Van Schoubroeck B，Mostmans W，Wuyts D，Verstappen D，Scholliers A，De Pooter D， Dhuyvetter D，Borghys H，Tuefferd M，Arnoult E，Hong J，Fanning G，Bollekens J，Urmaliya V，Teisman A，Horton H，Jonckers THM，Raboisson PJMB。
抽象

吡咯并[3,2-d]嘧啶被鉴定为一系列有效和选择性的TLR7激动剂。化合物针对其对TLR8的活性和选择性进行了优化。这表现出优于最近描述的具有残留TLR8活性的支架的优点，其可能不利于候选药物的耐受性。铅化合物54的口服给药有效地诱导小鼠和食蟹猴中的瞬时干扰素刺激基因（ISG）反应。我们的目标是通过高通量效应，全面限制细胞因子诱导，并展示了病毒性肝炎免疫治疗的潜力。

结论：
    28671847
DOI：
    10.1021 / acs.jmedchem.7b00365