Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer.

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 1 addressed hERG and physical property issues and led to clinical candidate AZD3514 (12), that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.