Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethy12-morpholino-4-oxo- 4H-chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3K beta and P13K delta for the Treatment of PTEN-Deficient Cancers

作者：Barlaam Bernard^*; Cosulich Sabina; Degorce Sebastien; Fitzek Martina; Green Stephen; Hancox Urs; Lambert van der Brempt Christine; Lohmann Jean Jacques; Maudet Mickael; Morgentin Remy; Pasquet Marie Jeanne; Peru Aurelien; Ple Patrick; Saleh Twana; Vautier Michel; Walker Mike; Ward Lara; Warin Nicolas

来源：Journal of Medicinal Chemistry, 2015, 58(2): 943-962.

DOI：10.1021/jm501629p

Several studies have highlighted the dependency of PTEN deficient tumors to PI3K beta activity and specific inhibition of PI3Kd has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3K beta/d inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.

• 出版日期2015-1-22