- Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies
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Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50?=?0.34?μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50?mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.
- Liang, Jun,Zhang, Birong,Labadie, Sharada,Ortwine, Daniel F.,Vinogradova, Maia,Kiefer, James R.,Gehling, Victor S.,Harmange, Jean-Christophe,Cummings, Richard,Lai, Tommy,Liao, Jiangpeng,Zheng, Xiaoping,Liu, Yichin,Gustafson, Amy,Van der Porten, Erica,Mao, Weifeng,Liederer, Bianca M.,Deshmukh, Gauri,Classon, Marie,Trojer, Patrick,Dragovich, Peter S.,Murray, Lesley
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p. 4036 - 4041
(2016/08/01)
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- PYRAZOLOPYRIMIDINES AS CYCLIN DEPENDENT KINASE INHIBITORS
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In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
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Page/Page column 38
(2008/06/13)
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- PYRAZOLOPYRIMIDINES AS CYCLIN DEPENDENT KINASE INHIBITORS
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In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
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- PYRAZOLOPYRIMIDINES AS CYCLIN-DEPENDENT KINASE INHIBITORS
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In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
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