新規Hedgehogシグナル阻害薬の合成研究

抄録

The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Abnormal activation of the Hh signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. The modification was started from the HTS hit thieno[3,2-c]quinoline-4-one derivative 1a, and focused on the enhancement of Gli reporter inhibitory activity and the improvement metabolic stability. Following optimization for the improvement of solubility was led to discover compound 3h (TAK-441) which was selected as a clinical candidate. The further SAR acquisition of TAK-441 brought to discover the several novel cores with potent Gli reporter inhibitory activity which was equal to that of TAK-441.

This report describes the details of the discovery of TAK-441 and the potent Hh signaling inhibitor with novel core skeletons.