1296271-07-2Relevant academic research and scientific papers
Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)- N, N -dimethyl-2-morpholino-4-oxo-4 H -chromene-6-carboxamide (AZD8186): A potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers
Barlaam, Bernard,Cosulich, Sabina,Degorce, Sébastien,Fitzek, Martina,Green, Stephen,Hancox, Urs,Lambert-Van Der Brempt, Christine,Lohmann, Jean-Jacques,Maudet, Micka?l,Morgentin, Rémy,Pasquet, Marie-Jeanne,Péru, Aurélien,Plé, Patrick,Saleh, Twana,Vautier, Michel,Walker, Mike,Ward, Lara,Warin, Nicolas
, p. 943 - 962 (2015/01/30)
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ 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 PI3Kβ/δ 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.
