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Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00365 David C. McGowan 1 , Florence Herschke 1 , Frederik Pauwels 1 , Bart Stoops 1 , Ilham Smyej 1 , Stefaan Last 1 , Serge Pieters 1 , Werner Embrechts 1 , Mourad Daoubi Khamlichi 2 , Tine Thoné 1 , Bertrand Van Schoubroeck 1 , Wendy Mostmans 1 , Debbie Wuyts 1 , Dorien Verstappen 1 , Annick Scholliers 1 , Dorien De Pooter 1 , Deborah Dhuyvetter 1 , Herman Borghys 1 , Marianne Tuefferd 1 , Eric Arnoult 3 , Jin Hong 4 , Gregory Fanning 1 , Jacques Bollekens 1 , Vijay Urmaliya 1 , Ard Teisman 1 , Helen Horton 1 , Tim H. M. Jonckers 1 , Pierre Raboisson 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00365 David C. McGowan 1 , Florence Herschke 1 , Frederik Pauwels 1 , Bart Stoops 1 , Ilham Smyej 1 , Stefaan Last 1 , Serge Pieters 1 , Werner Embrechts 1 , Mourad Daoubi Khamlichi 2 , Tine Thoné 1 , Bertrand Van Schoubroeck 1 , Wendy Mostmans 1 , Debbie Wuyts 1 , Dorien Verstappen 1 , Annick Scholliers 1 , Dorien De Pooter 1 , Deborah Dhuyvetter 1 , Herman Borghys 1 , Marianne Tuefferd 1 , Eric Arnoult 3 , Jin Hong 4 , Gregory Fanning 1 , Jacques Bollekens 1 , Vijay Urmaliya 1 , Ard Teisman 1 , Helen Horton 1 , Tim H. M. Jonckers 1 , Pierre Raboisson 1
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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.
中文翻译：
吡咯并[3,2 - d ]嘧啶Toll样受体7（TLR7）选择性激动剂的鉴定和优化
吡咯并[3，2- d ]嘧啶被鉴定为一系列新的有效和选择性的TLR7激动剂。针对化合物的活性和对TLR8的选择性进行了优化。与最近描述的具有残余TLR8活性的支架相比，这具有优势，该支架可能对候选药物的耐受性有害。口服给予先导化合物54可在小鼠和食蟹猴中有效诱导瞬时干扰素刺激基因（ISG）应答。我们旨在获得较高的首过效应，系统地限制细胞因子的诱导，并证明了病毒性肝炎免疫治疗的潜力。
更新日期：2017-07-14
中文翻译：
吡咯并[3,2 - d ]嘧啶Toll样受体7（TLR7）选择性激动剂的鉴定和优化
吡咯并[3，2- d ]嘧啶被鉴定为一系列新的有效和选择性的TLR7激动剂。针对化合物的活性和对TLR8的选择性进行了优化。与最近描述的具有残余TLR8活性的支架相比，这具有优势，该支架可能对候选药物的耐受性有害。口服给予先导化合物54可在小鼠和食蟹猴中有效诱导瞬时干扰素刺激基因（ISG）应答。我们旨在获得较高的首过效应，系统地限制细胞因子的诱导，并证明了病毒性肝炎免疫治疗的潜力。
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