4g11

Publication Abstract from PubMed

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kbeta isoform. The structure of compound 1 in PI3Kgamma was solved revealing a binding mode in agreement with the SAR observed on PI3Kbeta. 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.

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kbeta inhibitors.,Certal V, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme 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 Bioorg Med Chem Lett. 2012 Oct 15;22(20):6381-4. doi: 10.1016/j.bmcl.2012.08.072., Epub 2012 Aug 25. PMID:22981333^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.