Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

作者：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; Millan Jose Luis; Cosford Nicholas D P^*

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(17): 4308-4311.

DOI：10.1016/j.bmcl.2014.07.013

• Phosphatase
• Vascular calcification
• Probe compound
• ML086
• PHOSPHO1

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 (HIS) 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.

• 出版日期2014-9-1