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Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1.
Mould, Daniel P Bremberg, U Jordan, Allan M Geitmann, M McGonagle, Alison E Somervaille, Tim C P Spencer, Gary J Ogilvie, Donald J
Mould, Daniel P
Bremberg, U
Jordan, Allan M
Geitmann, M
McGonagle, Alison E
Somervaille, Tim C P
Spencer, Gary J
Ogilvie, Donald J
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Abstract
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1.
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2017-10-15
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Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1. 2017, 27 (20):4755-4759 Bioorg Med Chem Lett