Small Molecule Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Bioorg Med Chem Lett. 2012 Dec 15;22(24):7627-33. doi: 10.1016/j.bmcl.2012.10.008. Epub 2012 Oct 11.
Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
在此，我们描述了通过针对两种同工型之间不同的氨基酸残基（JAK1：E966；JAK2：D939）来获得相对于 JAK2 具有改善的 JAK1 选择性的 C-2 取代的咪唑并吡咯吡啶的成功尝试。还详细介绍了通过降低抑制剂的极性来提高细胞效力的尝试。还公开了与 JAK1 酶复合物的代表性抑制剂的 X 射线晶体结构。
