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

Yalda Bravo; Peter Teriete; Raveendra Panickar Dhanya; Russell Dahl; Pooi San Lee; Tina Kiffer-Moreira; Santhi Reddy Ganji; Eduard Sergienko; Layton H. Smith; Colin Farquharson; José Luis Millán; Nicholas D P Cosford

doi:10.1016/j.bmcl.2014.07.013

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

Yalda Bravo
, Peter Teriete
, Raveendra Panickar Dhanya
, Russell Dahl
, Pooi San Lee
, Tina Kiffer-Moreira
, Santhi Reddy Ganji
, Eduard Sergienko
, Layton H. Smith
, Colin Farquharson
, José Luis Millán
, Nicholas D P Cosford^*

^*Corresponding author for this work

Royal (Dick) School of Veterinary Studies

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	4308-4311
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	24
Issue number	17
Early online date	15 Jul 2014
DOIs	https://doi.org/10.1016/j.bmcl.2014.07.013
Publication status	Published - 12 Aug 2014

Keywords / Materials (for Non-textual outputs)

ML086
Phosphatase
PHOSPHO1
Probe compound
Vascular calcification

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10.1016/j.bmcl.2014.07.013

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Bravo, Y., Teriete, P., Dhanya, R. P., Dahl, R., Lee, P. S., Kiffer-Moreira, T., Ganji, S. R., Sergienko, E., Smith, L. H., Farquharson, C., Millán, J. L., & Cosford, N. D. P. (2014). Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1. Bioorganic & Medicinal Chemistry Letters, 24(17), 4308-4311. https://doi.org/10.1016/j.bmcl.2014.07.013

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title = "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.",

keywords = "ML086, Phosphatase, PHOSPHO1, Probe compound, Vascular calcification",

author = "Yalda Bravo and Peter Teriete and Dhanya, \{Raveendra Panickar\} and Russell Dahl and Lee, \{Pooi San\} and Tina Kiffer-Moreira and Ganji, \{Santhi Reddy\} and Eduard Sergienko and Smith, \{Layton H.\} and Colin Farquharson and Mill{\'a}n, \{Jos{\'e} Luis\} and Cosford, \{Nicholas D P\}",

year = "2014",

month = aug,

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doi = "10.1016/j.bmcl.2014.07.013",

language = "English",

volume = "24",

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T1 - Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

AU - Bravo, Yalda

AU - Teriete, Peter

AU - Dhanya, Raveendra Panickar

AU - Dahl, Russell

AU - Lee, Pooi San

AU - Kiffer-Moreira, Tina

AU - Ganji, Santhi Reddy

AU - Sergienko, Eduard

AU - Smith, Layton H.

AU - Farquharson, Colin

AU - Millán, José Luis

AU - Cosford, Nicholas D P

PY - 2014/8/12

Y1 - 2014/8/12

N2 - 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.

AB - 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.

KW - ML086

KW - Phosphatase

KW - PHOSPHO1

KW - Probe compound

KW - Vascular calcification

UR - https://www.scopus.com/pages/publications/84906933596

U2 - 10.1016/j.bmcl.2014.07.013

DO - 10.1016/j.bmcl.2014.07.013

M3 - Article

SN - 0960-894X

VL - 24

SP - 4308

EP - 4311

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 17

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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