Beswick Paul, Charrier Nicolas, Clarke Brian, Demont Emmanuel, Dingwall Colin, Dunsdon Rachel, Faller Andrew, Gleave Robert, Hawkins Julie, Hussain Ishrut, Johnson Christopher N, MacPherson David, Maile Graham, Matico Rosalie, Milner Peter, Mosley Julie, Naylor Alan, O'Brien Alistair, Redshaw Sally, Riddell David, Rowland Paul, Skidmore John, Soleil Virginie, Smith Kathrine J, Stanway Steven, Stemp Geoffrey, Stuart Alistair, Sweitzer Sharon, Theobald Pam, Vesey David, Walter Daryl S, Ward John, Wayne Gareth
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. doi: 10.1016/j.bmcl.2007.12.020. Epub 2007 Dec 15.
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
本文聚焦于在X射线晶体学的支持下，对先前从一个聚焦文库中获得的羟乙胺（HEA）BACE-1抑制剂进行进一步优化。对我们抑制剂的非关键侧进行优化，并引入与Asn-294结合的六元磺内酰胺取代基以及在C-2位引入氟，得到了在基于细胞的检测中具有纳摩尔效力的衍生物。
