Bisphenol Derivatives Modulating Androgen Receptor Activity
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Solution Overview
Problem
Current treatments for prostate and ovarian cancers, particularly androgen-independent prostate cancer, are limited by the ineffectiveness of existing antiandrogen therapies due to poor affinity and mutations, as well as the inability to target constitutively active androgen receptor splice variants, leading to disease progression.
Innovation Solution
Development of compounds that modulate androgen receptor (AR) activity, specifically inhibiting AR activity to block tumor growth in the presence and absence of androgens, which can be used to treat various cancers including prostate, breast, and ovarian cancers by targeting the N-terminal domain of the AR.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antiandrogen therapies are used, then androgen receptor activity is blocked, but the treatment becomes ineffective due to poor affinity and mutations in androgen-independent prostate cancer
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of antiandrogen compounds to achieve high-affinity binding to the androgen receptor. The compounds of Formula I and related structures are designed with specific molecular parameters (substituents R1-R6, ring structures, stereochemistry) that optimize binding affinity to the AR ligand-binding domain, thereby maintaining effectiveness against mutated and constitutively active AR splice variants that render conventional therapies ineffective
Solution Approach 2:
The patent achieves universality by developing compounds that can target multiple forms of the androgen receptor simultaneously - including wild-type AR, mutated AR, and constitutively active AR splice variants (such as AR-V7, AR-V9, AR-V567es). The compounds of Formula I are designed to bind to the conserved ligand-binding domain across all these variants, providing broad-spectrum activity against androgen-dependent and androgen-independent prostate cancer
2Productivity
If androgen ablation therapy is used, then tumor burden is temporarily reduced, but the disease progresses to androgen-independent state within two years
Solution Approach 1:
The patent applies preliminary action by using compounds of Formula I that can prevent the development of androgen-independent disease or delay its onset. These high-affinity antiandrogens are designed to maintain sustained suppression of AR activity over long periods, potentially preventing the adaptive resistance that typically develops within two years of conventional androgen ablation therapy
Solution Approach 2:
The patent achieves continuity of useful action by developing compounds designed for long-term continuous administration that maintain constant high-affinity binding to the androgen receptor. The compounds of Formula I are intended for chronic therapy to continuously suppress AR signaling, preventing the intermittent or waning effect seen with conventional therapies and thereby extending the duration of therapeutic benefit beyond the typical two-year progression to androgen-independent disease
3Reliability
If high-affinity binding compounds are developed, then AR activity is effectively inhibited, but the complexity of compound structure increases
Solution Approach 1:
The patent systematically applies parameter changes by defining specific ranges and options for molecular parameters in Formula I (substituents R1-R6 being C1-C10 alkyl, cyclic groups, aromatic groups; q, r, s, t being 0-7; n being 0-8). This structured approach to parameter optimization allows for high-affinity binding while maintaining a manageable framework for compound design and synthesis, balancing effectiveness with structural complexity
Data Source
AI summary
This invention provides bisphenol derivatives having a structure of formula 1. Said compounds are modulators of the androgen receptor activity and are useful in the treatment of various diseases, including prostate cancer, breast cancer, ovarian cancer, endometrial cancer, acne, ovarian cysts, polycystic ovarian disease, age-related macular degeneration, precocious puberty, hirsutism and hair loss.