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 journalArticle

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 languageEnglish (US)
Pages (from-to)6381-6384
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number20
DOIs
StatePublished - Oct 15 2012
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinases
Amides
Derivatives
Anilides
Pyrimidinones
Biological Availability
Assays
Prostatic Neoplasms
Protein Isoforms
Cells
Cell Line

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

Cite this

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors. / Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean Christophe; Delorme, Cécile; Karlsson, Andreas; Abecassis, Pierre Yves; Vincent, Loic; Bonnevaux, Hélène; Nicolas, Jean Paul; Morales, Renaud; Michot, Nadine; Vade, Isabelle; Louboutin, Audrey; Perron, Sébastien; Doerflinger, Gilles; Tric, Bernadette; Monget, Sylvie; Lengauer, Christoph; Schio, Laurent.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 20, 15.10.2012, p. 6381-6384.

Research output: Contribution to journalArticle

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
Certal, Victor ; Halley, Frank ; Virone-Oddos, Angela ; Thompson, Fabienne ; Filoche-Rommé, Bruno ; El-Ahmad, Youssef ; Carry, Jean Christophe ; Delorme, Cécile ; Karlsson, Andreas ; Abecassis, Pierre Yves ; Vincent, Loic ; Bonnevaux, Hélène ; Nicolas, Jean Paul ; Morales, Renaud ; Michot, Nadine ; Vade, Isabelle ; Louboutin, Audrey ; Perron, Sébastien ; Doerflinger, Gilles ; Tric, Bernadette ; Monget, Sylvie ; Lengauer, Christoph ; Schio, Laurent. / Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6- dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 20. pp. 6381-6384.
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