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, Stanislawski Pauline C, 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):969-75. doi: 10.1016/j.bmcl.2014.11.018. Epub 2014 Nov 15.
Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compound 1a (9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one) was identified as an inhibitor of A and B strains of RSV targeting the fusion glycoprotein. SAR was developed by systematic exploration of the phenyl (R(1)) and benzoyl (R(2)) groups. Furthermore, introduction of a nitrogen at the 8-position of the tricyclic core resulted in active analogues with improved properties (aqueous solubility, protein binding and logD) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compound 17).
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。化合物1a（9b-(4-氯苯基)-1-(4-氟苯甲酰基)-1,2,3,9b-四氢-5H-咪唑并[2,1-a]异吲哚-5-酮）被鉴定为靶向融合糖蛋白的呼吸道合胞病毒A和B株的抑制剂。通过对苯基（R(1)）和苯甲酰基（R(2)）基团的系统探索建立了构效关系。此外，在三环核心的8位引入一个氮原子，得到了具有改善性质（水溶性、蛋白质结合和logD）和优异大鼠药代动力学（例如，化合物17的大鼠口服生物利用度为89%）的活性类似物。
