当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Discovery of GS-7682, a Novel 4′-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-17 , DOI: 10.1021/acs.jmedchem.4c00899 Dustin S Siegel 1 , Hon C Hui 1 , Jared Pitts 1 , Meghan S Vermillion 1, 2 , Kazuya Ishida 1 , Davin Rautiola 1 , Michael Keeney 1 , Hammad Irshad 2 , Lijun Zhang 1 , Kwon Chun 1 , Gregory Chin 1 , Bindu Goyal 1 , Edward Doerffler 1 , Hai Yang 1 , Michael O Clarke 1 , Chris Palmiotti 1 , Arya Vijjapurapu 1 , Nicholas C Riola 1 , Kirsten Stray 1 , Eisuke Murakami 1 , Bin Ma 1 , Ting Wang 1 , Xiaofeng Zhao 1 , Yili Xu 1 , Gary Lee 1 , Bruno Marchand 1 , Minji Seung 1 , Arabinda Nayak 1 , Adrian Tomkinson 1 , Nani Kadrichu 3 , Scott Ellis 1 , Ona Barauskas 1 , Joy Y Feng 1 , Jason K Perry 1 , Michel Perron 1 , John P Bilello 1 , Philip J Kuehl 2 , Raju Subramanian 1 , Tomas Cihlar 1 , Richard L Mackman 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-17 , DOI: 10.1021/acs.jmedchem.4c00899 Dustin S Siegel 1 , Hon C Hui 1 , Jared Pitts 1 , Meghan S Vermillion 1, 2 , Kazuya Ishida 1 , Davin Rautiola 1 , Michael Keeney 1 , Hammad Irshad 2 , Lijun Zhang 1 , Kwon Chun 1 , Gregory Chin 1 , Bindu Goyal 1 , Edward Doerffler 1 , Hai Yang 1 , Michael O Clarke 1 , Chris Palmiotti 1 , Arya Vijjapurapu 1 , Nicholas C Riola 1 , Kirsten Stray 1 , Eisuke Murakami 1 , Bin Ma 1 , Ting Wang 1 , Xiaofeng Zhao 1 , Yili Xu 1 , Gary Lee 1 , Bruno Marchand 1 , Minji Seung 1 , Arabinda Nayak 1 , Adrian Tomkinson 1 , Nani Kadrichu 3 , Scott Ellis 1 , Ona Barauskas 1 , Joy Y Feng 1 , Jason K Perry 1 , Michel Perron 1 , John P Bilello 1 , Philip J Kuehl 2 , Raju Subramanian 1 , Tomas Cihlar 1 , Richard L Mackman 1
Affiliation
|
Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4′-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3–46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54–61 nM), and enterovirus (EC50 = 83–90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5′-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2′,3′-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.
中文翻译：
GS-7682 的发现，一种新型 4'-氰基修饰的 C-核苷前药，具有广泛的抗肺炎病毒和小核糖核酸病毒活性，并对 RSV 感染的非洲绿猴有效
急性呼吸道病毒感染，例如肺病毒和呼吸道小核糖核酸病毒感染，会加剧慢性阻塞性肺病和哮喘患者的病情。一项针对呼吸道合胞病毒 (RSV) 的研究计划发现了 GS-7682 ( 1 )，这是一种 4'-CN-4-aza-7,9-二脱氮杂腺苷C -核苷 GS-646089 ( 2 )的新型氨基磷酸酯前药）对 RSV (EC 50 = 3–46 nM)、人偏肺病毒 (EC 50 = 210 nM)、人鼻病毒 (EC 50 = 54–61 nM) 和肠道病毒 (EC 50 = 83–90 nM) 具有广泛的抗病毒活性。针对细胞效力和肺细胞代谢的前药优化确定了 5'-甲基[( S )-羟基（苯氧基）磷酰] -l-丙氨酸与 2',3'-二异丁酸酯前体组合是高水平细胞内三磷酸盐形成的最佳选择体外和体内。图1表明，每天一次通过气管内雾化气雾剂给药时，RSV感染的非洲绿猴下呼吸道的病毒载量显着减少。总之，这些发现支持对1及其类似物作为肺炎病毒和小核糖核酸病毒的潜在疗法的额外评估。
更新日期：2024-07-17
中文翻译：
GS-7682 的发现，一种新型 4'-氰基修饰的 C-核苷前药，具有广泛的抗肺炎病毒和小核糖核酸病毒活性，并对 RSV 感染的非洲绿猴有效
急性呼吸道病毒感染，例如肺病毒和呼吸道小核糖核酸病毒感染，会加剧慢性阻塞性肺病和哮喘患者的病情。一项针对呼吸道合胞病毒 (RSV) 的研究计划发现了 GS-7682 ( 1 )，这是一种 4'-CN-4-aza-7,9-二脱氮杂腺苷C -核苷 GS-646089 ( 2 )的新型氨基磷酸酯前药）对 RSV (EC 50 = 3–46 nM)、人偏肺病毒 (EC 50 = 210 nM)、人鼻病毒 (EC 50 = 54–61 nM) 和肠道病毒 (EC 50 = 83–90 nM) 具有广泛的抗病毒活性。针对细胞效力和肺细胞代谢的前药优化确定了 5'-甲基[( S )-羟基（苯氧基）磷酰] -l-丙氨酸与 2',3'-二异丁酸酯前体组合是高水平细胞内三磷酸盐形成的最佳选择体外和体内。图1表明，每天一次通过气管内雾化气雾剂给药时，RSV感染的非洲绿猴下呼吸道的病毒载量显着减少。总之，这些发现支持对1及其类似物作为肺炎病毒和小核糖核酸病毒的潜在疗法的额外评估。
京公网安备 11010802027423号