1383973-89-4Relevant academic research and scientific papers
Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers
Certal, Victor,Carry, Jean-Christophe,Halley, Frank,Virone-Oddos, Angela,Thompson, Fabienne,Filoche-Rommé, Bruno,El-Ahmad, Youssef,Karlsson, Andreas,Charrier, Véronique,Delorme, Cécile,Rak, Alexey,Abecassis, Pierre-Yves,Amara, Céline,Vincent, Lo?c,Bonnevaux, Hélène,Nicolas, Jean-Paul,Mathieu, Magali,Bertrand, Thomas,Marquette, Jean-Pierre,Michot, Nadine,Benard, Tsiala,Perrin, Marc-Antoine,Lemaitre, Olivier,Guerif, Stephane,Perron, Sébastien,Monget, Sylvie,Gruss-Leleu, Florence,Doerflinger, Gilles,Guizani, Houlfa,Brollo, Maurice,Delbarre, Laurence,Bertin, Luc,Richepin, Patrick,Loyau, Véronique,Garcia-Echeverria, Carlos,Lengauer, Christoph,Schio, Laurent
, p. 903 - 920 (2014/03/21)
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kβ-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kβ inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2- oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110β with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.
NOVEL PYRIMIDINE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS
-
Paragraph 2701-2707, (2013/10/22)
The present invention relates to novel chemical compounds derived from pyrimidines, to the method for preparing same, to the novel intermediates obtained, to the use thereof as drugs, to the pharmaceutical compositions containing same, and to the therapeutic use thereof as AKT inhibitors.
