Bisphenol Ether Compounds Targeting Androgen Receptor N-Terminal Domain

The patent modifies the chemical structure of antiandrogen compounds by introducing a chlorohydrin moiety at the C-19 position of the steroid nucleus. This structural parameter change enables the compounds to effectively target both wild-type and mutated AR splice variants, overcoming the poor binding affinity issue of existing antiandrogens and improving treatment efficacy for castration-resistant prostate cancer

The invention introduces a specific functional group (chlorohydrin moiety) at a precise location (C-19 position) of the steroid molecule. This localized modification targets the N-terminal domain of the androgen receptor, providing selective high-affinity binding to AR splice variants while maintaining the overall steroid framework, thereby resolving the contradiction between binding affinity and treatment efficacy

The patent designs antiandrogen compounds with a chlorohydrin moiety that can universally bind to the N-terminal domain of all androgen receptor variants, including those lacking the ligand-binding domain. This multi-functional targeting capability allows a single compound to effectively inhibit both classical AR and AR splice variants, overcoming the limitation of existing antiandrogens that only target the ligand-binding domain

Instead of targeting the ligand-binding domain as conventional antiandrogens do, the invention inverts the targeting approach by directing the chlorohydrin moiety to bind to the N-terminal domain of the androgen receptor. This inverted targeting strategy enables effective inhibition of AR splice variants that lack the ligand-binding domain, thereby improving both adaptability and inhibition effectiveness