Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors

• Published in: European journal of medicinal chemistry Vol. 180; pp. 72 - 85
• Main Authors: Zhan, Wenhu, Che, Jinxin, Xu, Lei, Wu, Yizhe, Hu, Xiaobei, Zhou, Yubo, Cheng, Gang, Hu, Yongzhou, Dong, Xiaowu, Li, Jia
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.10.2019
• Subjects: Akt inhibitor; Antitumor; Pyrazole-thiophene derivatives; Pyrazole-thiophene derivatives; Akt inhibitor; Antitumor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.07.017

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development. [Display omitted] •Compound 1d and 1o with good Akt inhibitory activities were obtained on the basis of conformational restriction strategy.•Compound 1d and 1o showed excellent in vitro antitumor effect.•Compound 1o exhibited good PK profiles and a 40% tumor growth inhibition in MM1S xenograft tumor model.