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

ABSTRACT: 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.

SUBMITTER: Bravo Y

PROVIDER: S-EPMC4170737 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Bravo Yalda Y Teriete Peter P Dhanya Raveendra-Panickar RP Dahl Russell R Lee Pooi San PS Kiffer-Moreira Tina T Ganji Santhi Reddy SR Sergienko Eduard E Smith Layton H LH Farquharson Colin C Millán José Luis JL Cosford Nicholas D P ND

Bioorganic & medicinal chemistry letters 20140715 17

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 meas ...[more]

PMID: 25124115

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