Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Victor Certal; Frank Halley; Angela Virone-Oddos; Fabienne Thompson; Bruno Filoche-Rommé; Youssef El-Ahmad; Jean Christophe Carry; Cécile Delorme; Andreas Karlsson; Pierre Yves Abecassis; Loic Vincent; Hélène Bonnevaux; Jean Paul Nicolas; Renaud Morales; Nadine Michot; Isabelle Vade; Audrey Louboutin; Sébastien Perron; Gilles Doerflinger; Bernadette Tric; Sylvie Monget; Christoph Lengauer; Laurent Schio

doi:10.1016/j.bmcl.2012.08.072

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Victor Certal, Frank Halley, Angela Virone-Oddos, Fabienne Thompson, Bruno Filoche-Rommé, Youssef El-Ahmad, Jean Christophe Carry, Cécile Delorme, Andreas Karlsson, Pierre Yves Abecassis, Loic Vincent, Hélène Bonnevaux, Jean Paul Nicolas, Renaud Morales, Nadine Michot, Isabelle Vade, Audrey Louboutin, Sébastien Perron, Gilles Doerflinger, Bernadette TricSylvie Monget, Christoph Lengauer, Laurent Schio

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

22 Scopus citations

Abstract

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. 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.

Original language	English (US)
Pages (from-to)	6381-6384
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2012.08.072
State	Published - Oct 15 2012
Externally published	Yes

Keywords

Kinase inhibitor
pAkt
PI3Kβ
PTEN
Pyrimidone anilide

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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10.1016/j.bmcl.2012.08.072

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Certal, V., Halley, F., Virone-Oddos, A., Thompson, F., Filoche-Rommé, B., El-Ahmad, Y., Carry, J. C., Delorme, C., Karlsson, A., Abecassis, P. Y., Vincent, L., Bonnevaux, H., Nicolas, J. P., Morales, R., Michot, N., Vade, I., Louboutin, A., Perron, S., Doerflinger, G., ... Schio, L. (2012). Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors. Bioorganic and Medicinal Chemistry Letters, 22(20), 6381-6384. https://doi.org/10.1016/j.bmcl.2012.08.072

Certal, V, Halley, F, Virone-Oddos, A, Thompson, F, Filoche-Rommé, B, El-Ahmad, Y, Carry, JC, Delorme, C, Karlsson, A, Abecassis, PY, Vincent, L, Bonnevaux, H, Nicolas, JP, Morales, R, Michot, N, Vade, I, Louboutin, A, Perron, S, Doerflinger, G, Tric, B, Monget, S, Lengauer, C & Schio, L 2012, 'Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 20, pp. 6381-6384. https://doi.org/10.1016/j.bmcl.2012.08.072

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abstract = "From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. 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.",

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author = "Victor Certal and Frank Halley and Angela Virone-Oddos and Fabienne Thompson and Bruno Filoche-Romm{\'e} and Youssef El-Ahmad and Carry, {Jean Christophe} and C{\'e}cile Delorme and Andreas Karlsson and Abecassis, {Pierre Yves} and Loic Vincent and H{\'e}l{\`e}ne Bonnevaux and Nicolas, {Jean Paul} and Renaud Morales and Nadine Michot and Isabelle Vade and Audrey Louboutin and S{\'e}bastien Perron and Gilles Doerflinger and Bernadette Tric and Sylvie Monget and Christoph Lengauer and Laurent Schio",

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doi = "10.1016/j.bmcl.2012.08.072",

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AU - Halley, Frank

AU - Virone-Oddos, Angela

AU - Thompson, Fabienne

AU - Filoche-Rommé, Bruno

AU - El-Ahmad, Youssef

AU - Carry, Jean Christophe

AU - Delorme, Cécile

AU - Karlsson, Andreas

AU - Abecassis, Pierre Yves

AU - Vincent, Loic

AU - Bonnevaux, Hélène

AU - Nicolas, Jean Paul

AU - Morales, Renaud

AU - Michot, Nadine

AU - Vade, Isabelle

AU - Louboutin, Audrey

AU - Perron, Sébastien

AU - Doerflinger, Gilles

AU - Tric, Bernadette

AU - Monget, Sylvie

AU - Lengauer, Christoph

AU - Schio, Laurent

PY - 2012/10/15

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KW - PTEN

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Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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