Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3K[beta] inhibitors
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3K[beta] isoform. The structure of compound 1 in PI3K[gamma] was solved revealing a binding mode in agreement with the SAR observed on PI3K[beta]. These comp...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-10, Vol.22 (20), p.6381-6384 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Certal, Victor Halley, Frank Virone-Oddos, Angela Thompson, Fabienne Filoche-Romme, Bruno El-Ahmad, Youssef Carry, Jean-Christophe Delorme, Cecile Karlsson, Andreas Abecassis, Pierre-Yves Vincent, Loic Bonnevaux, Helene Nicolas, Jean-Paul Morales, Renaud Michot, Nadine Vade, Isabelle Louboutin, Audrey Perron, Sebastien Doerflinger, Gilles Tric, Bernadette Monget, Sylvie Lengauer, Christoph Schio, Laurent |
| description | From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3K[beta] isoform. The structure of compound 1 in PI3K[gamma] was solved revealing a binding mode in agreement with the SAR observed on PI3K[beta]. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study. |
| doi_str_mv | 10.1016/j.bmcl.2012.08.072 |
| format | Article |
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| ispartof | Bioorganic & medicinal chemistry letters, 2012-10, Vol.22 (20), p.6381-6384 |
| issn | 0960-894X |
| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Indexing in process |
| title | Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3K[beta] inhibitors |
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