Bond Silas, Draffan Alistair G, Fenner Jennifer E, Lambert John, Lim Chin Yu, Lin Bo, Luttick Angela, Mitchell Jeffrey P, Morton Craig J, Nearn Roland H, Sanford Vanessa, Anderson Kelly H, Mayes Penelope A, Tucker Simon P
Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
Bioorg Med Chem Lett. 2015 Feb 15;25(4):976-81. doi: 10.1016/j.bmcl.2014.11.024. Epub 2014 Nov 14.
Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones with general structure 1 were previously identified as promising inhibitors of RSV targeting the fusion glycoprotein. In particular, the introduction of a nitrogen at the 8-position of the tricyclic core yielded lead compounds 2 and 3. Extensive exploration of the R(2) group established that certain heterocyclic amides conferred potent RSV A&B activity and a good balance of physicochemical and pharmacokinetic properties. The antiviral activity was found to reside in a single enantiomer and compound 33a, (9bS)-9b-(4-chlorophenyl)-1-(pyridin-3-ylcarbonyl)-1,2,3,9b-tetrahydro-5H-imidazo[1',2':1,2]pyrrolo[3,4-c]pyridin-5-one (known as BTA9881), was identified as a candidate for preclinical development.
呼吸道合胞病毒（RSV）是婴幼儿和成人呼吸道感染的主要病因。先前已确定具有通式1结构的1,2,3,9b-四氢-5H-咪唑并[2,1-a]异吲哚-5-酮是靶向融合糖蛋白的有前景的RSV抑制剂。特别是，在三环核心的8位引入氮原子得到了先导化合物2和3。对R(2)基团的广泛探索表明，某些杂环酰胺具有强效的RSV A&B活性，并且在物理化学和药代动力学性质方面具有良好的平衡。发现抗病毒活性存在于单一对映体中，化合物33a，即(9bS)-9b-(4-氯苯基)-1-(吡啶-3-基羰基)-1,2,3,9b-四氢-5H-咪唑并[1',2':1,2]吡咯并[3,4-c]吡啶-5-酮（称为BTA9881），被确定为临床前开发的候选药物。
