Diarylhydantoin AR Antagonists for Hormone-Refractory Prostate Cancer
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Solution Overview
Problem
Current antiandrogens used to treat prostate cancer, such as bicalutamide, are ineffective against hormone refractory prostate cancer due to weak antagonistic activities and strong agonistic activities when the androgen receptor (AR) is overexpressed, leading to disease progression.
Innovation Solution
Development of diarylhydantoin compounds with strong antagonistic activities and minimal agonistic activities against AR, synthesized through specific chemical pathways, to inhibit the growth of hormone refractory prostate cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiandrogens (e.g., bicalutamide) are used to treat prostate cancer, then they provide inhibitory effect on AR in hormone sensitive prostate cancer, but they fail to suppress AR when cancer becomes hormone refractory due to weak antagonistic activities and strong agonistic activities
Solution Approach 1:
The patent modifies the chemical structure of antiandrogen compounds by changing parameters such as introducing specific aromatic rings (e.g., naphthyridine, pyridine, triazine cores) with particular substituents at defined positions. This structural parameter change transforms the compound from having weak antagonistic/strong agonistic properties to achieving strong antagonistic activity with minimal agonistic activity, thereby resolving the contradiction in hormone refractory prostate cancer treatment
Solution Approach 2:
The invention creates composite molecular structures combining specific aromatic ring systems (naphthyridine, pyridine, triazine) with functional groups (carboxylic acid, ester, amide, urea, carbamate) to form novel diarylhydantoin compounds. This composite approach integrates multiple structural motifs to achieve the desired pharmacological profile of strong AR antagonism without agonistic effects
2Reliability
If androgen deprivation therapy (castration and antiandrogens) is administered to treat advanced prostate cancer, then AR activity is reduced initially, but the cancer becomes hormone refractory and progresses
Solution Approach 1:
The patent develops a series of diarylhydantoin compounds that continuously and potently inhibit AR activity without the temporal limitation of current antiandrogens. The compounds maintain stable antagonistic activity over time, preventing the transition from hormone-sensitive to hormone-refractory state and extending the duration of effective AR suppression throughout the disease course
Solution Approach 2:
By systematically modifying molecular parameters (introducing different aromatic cores, varying substituent types and positions), the patent creates compounds with enhanced pharmacokinetic properties and sustained AR binding affinity. This parameter optimization ensures prolonged duration of action compared to conventional antiandrogens that lose efficacy over time
3Measurement precision
If existing antiandrogen compounds are synthesized and tested, then their antagonistic and agonistic activities can be evaluated, but the process is time-consuming and requires extensive testing
Solution Approach 1:
The patent segments the evaluation process into structured tiers (Tier 1-6) based on predicted activity levels, allowing systematic assessment of compounds in groups rather than individually. This segmentation enables parallel testing and prioritization, reducing overall time while maintaining precise measurement of antagonistic and agonistic activities through standardized assays
Solution Approach 2:
The invention incorporates feedback mechanisms where initial screening results guide subsequent testing priorities and compound optimization. Compounds showing promising antagonistic activity with low agonistic activity in preliminary tests are advanced for detailed characterization, while less promising candidates are eliminated early, efficiently allocating testing resources and time
Data Source
AI summary
The present invention relates to diarylhydantoin compounds, including diarylthiohydantoins, and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.