苯并异噻唑啉酮作为PHOSPHO1选择性抑制剂的设计、合成与评价
Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1.
作者信息
Bravo Yalda, Teriete Peter, Dhanya Raveendra-Panickar, Dahl Russell, Lee Pooi San, Kiffer-Moreira Tina, Ganji Santhi Reddy, Sergienko Eduard, Smith Layton H, Farquharson Colin, Millán José Luis, Cosford Nicholas D P
机构信息
Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
出版信息
Bioorg Med Chem Lett. 2014 Sep 1;24(17):4308-11. doi: 10.1016/j.bmcl.2014.07.013. Epub 2014 Jul 15.
We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086.
我们报告了一系列苯并异噻唑啉酮对PHOSPHO1的抑制作用的发现与表征，PHOSPHO1是一种新发现的与骨骼矿化和软组织骨化异常有关的可溶性磷酸酶。对小分子文库进行高通量筛选（HTS），从而确定苯并异噻唑啉酮是PHOSPHO1的有效且选择性抑制剂。确定了活性的关键结构要求，随后对这些化合物进行衍生化，并测定其体外活性和ADME参数，包括代谢稳定性和通透性。基于其总体特征，选择苯并异噻唑啉酮类似物2q作为MLPCN探针ML086。
Zotero 插件