Barlaam Bernard, Cosulich Sabina, Degorce Sébastien, Fitzek Martina, Green Stephen, Hancox Urs, Lambert-van der Brempt Christine, Lohmann Jean-Jacques, Maudet Mickaël, Morgentin Rémy, Pasquet Marie-Jeanne, Péru Aurélien, Plé Patrick, Saleh Twana, Vautier Michel, Walker Mike, Ward Lara, Warin Nicolas
Centre de Recherches, AstraZeneca , Z. I. La Pompelle, Chemin de Vrilly, BP 1050, 51689 Reims Cedex 2, France.
J Med Chem. 2015 Jan 22;58(2):943-62. doi: 10.1021/jm501629p. Epub 2015 Jan 7.
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.
多项研究强调了PTEN缺陷型肿瘤对PI3Kβ活性的依赖性，并且已表明PI3Kδ的特异性抑制对人类B细胞癌具有活性。我们描述了一系列8-(1-苯胺基)乙基)-2-吗啉代-4-氧代-4H-色烯-6-甲酰胺作为PI3Kβ/δ抑制剂的发现和优化过程，这导致了临床候选药物13（也称为AZD8186）的发现。基于与先前使用的吡啶并[1,2-a]嘧啶-4-酮核心相比，色烯-4-酮核心的亲脂性较低，该系列化合物显示出高代谢稳定性和适合口服给药的物理性质。化合物13在口服给药后对携带PTEN缺陷型PC3前列腺肿瘤的小鼠中的p-Akt具有深刻的药效学调节作用，并在小鼠PTEN缺陷型PC3前列腺肿瘤异种移植模型中显示出对肿瘤生长的完全抑制。13被选为治疗PTEN缺陷型癌症的临床候选药物，并且最近已进入I期临床试验。
