Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1.
Authors
Mould, Daniel PBremberg, U
Jordan, Allan M
Geitmann, M
Maiques-Diaz, Alba
McGonagle, Alison E
Small, Helen F
Somervaille, Tim C P
Ogilvie, Donald J
Affiliation
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BXIssue Date
2017-05-08
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A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.Citation
Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1. 2017 Bioorg. Med. Chem. Lett.Journal
Bioorganic & Medicinal Chemistry LettersDOI
10.1016/j.bmcl.2017.05.018PubMed ID
28545974Type
ArticleLanguage
enISSN
1464-3405ae974a485f413a2113503eed53cd6c53
10.1016/j.bmcl.2017.05.018
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