Fernando Blanco;D. Clive Williams;Gemma Karena Kinsella;Wiliam Nicholas Jagoe;Mary Jane Meegan;Darren Fayne;Billy Egan;Miriam Carr;David George Lloyd;Laura Caboni
发明人:
David George Lloyd,Darren Fayne,Mary Jane Meegan,Miriam Carr,Gemma Karena Kinsella,Laura Caboni,Wiliam Nicholas Jagoe,Billy Egan,Fernando Blanco,D. Clive Williams
申请号：
US14360081
公开号：
US09296716B2
申请日:
2012.11.23
申请国别(地区):
US
年份:
2016
代理人:
摘要：
Non ligand binding pocket antagonists for the human androgen receptor. The androgen receptor (AR) is a member of the Nuclear Receptor (NR) family and its role is to modulate the biological effects of the endogenous androgens, testosterone (tes) and dihydrotestosterone (DHT). Synthetic androgens and anti-androgens have therapeutic value in the treatment of various androgen dependent conditions, from regulation of male fertility to prostate cancer. Current treatment of prostate cancer (PCa) typically involves administration of ‘classical’ antiandrogens, competitive inhibitors of natural AR ligands, DHT and tes, for the ligand binding pocket (LBP) in the C-terminal ligand binding domain (LBD) of the AR. However, prolonged LBP-targeting can often lead to androgen resistance and alternative therapies and therapeutic strategies are urgently required. Disclosed herein are a class of non-steroidal, small molecule AR antagonists which inhibit the transcriptional activity of the AR by non LBP-mediated modulation. The novel class reported demonstrates full (‘true’) antagonism in AR with low micromolar potency, high selectivity over both the Estrogen Receptors alpha and beta (ERα and ERβ) and the Glucocorticoid Receptor (GR) and only micromolar partial antagonism in the Progesterone Receptor (PR). Data provide compelling evidence for such non-LBP intervention as an alternative approach to classical PCa therapy. (Formula I).
