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

Abstract

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.

• Authors: Wenhu Zhan, Jinxin Che, Lei Xu, Yizhe Wu, Xiaobei Hu, Yubo Zhou, Gang Cheng, Yongzhou Hu, Xiaowu Dong, Jia Li
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 180 Pg. 72-85 (Oct 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31301565 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Pyrazoles
• Thiophenes
• pyrazole
• Proto-Oncogene Proteins c-akt

Topics

• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• HCT116 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microsomes, Liver (chemistry, metabolism)
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrazoles (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship
• Thiophenes (administration & dosage, chemistry, pharmacology)
• Tumor Cells, Cultured