Selective Androgen Receptor Modulators Tissue-Specific Design
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Solution Overview
Problem
Current androgen therapies often face challenges in balancing the benefits of androgen agonists with the undesirable effects such as prostate stimulation, acne, and masculinization, necessitating the development of novel androgen receptor modulators that selectively target tissues without stimulating the prostate.
Innovation Solution
Development of specific compounds like (R)-4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-2-(trifluoromethyl)benzonitrile and its analogs, which act as selective androgen receptor modulators (SARMs) to modulate androgen receptor activity, thereby minimizing prostate stimulation while maintaining muscle growth and other beneficial effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If androgen agonists are used to promote muscle growth and bone density, then anabolic effects are improved, but prostate stimulation and masculinization side effects worsen
Solution Approach 1:
The patent applies local quality by designing SARM compounds with specific molecular structures that confer tissue-selective androgen receptor modulation. Different compounds in the series exhibit preferential binding affinity for AR in muscle and bone tissues versus prostate tissue, achieving localized anabolic effects while minimizing prostate stimulation through structural differentiation rather than uniform androgenic activity
Solution Approach 2:
The patent employs parameter changes by systematically modifying chemical parameters of the androgen receptor modulators, including variations in R-groups, stereochemistry, and molecular substitutions across compound series. These parameter modifications tune the pharmacological profile to enhance muscle selectivity while reducing prostate androgenic stimulation, transforming the general androgenic response into a selective tissue-specific effect
2Object-generated harmful factors
If androgen antagonists are used to block prostate stimulation, then prostate effects are reduced, but muscle growth benefits are lost
Solution Approach 1:
The patent applies segmentation by dividing the androgen receptor modulation function into tissue-specific segments through the SARM compound design. Rather than using a single antagonist that blocks all androgen receptor activity, the invention creates compounds that segment the androgenic response to activate AR in muscle and bone while leaving prostate AR unaffected, achieving functional separation of androgen effects across different tissues
Solution Approach 2:
The patent uses SARM compounds as intermediary substances that mediate between complete androgen agonism and complete antagonism. These intermediaries provide partial agonist activity in muscle and bone tissues while acting as functional antagonists in prostate tissue, serving as a bridge that selectively permits androgen signaling only in desired tissues without requiring full agonist or antagonist activity across all tissues
Data Source
AI summary
This invention provides compounds as described herein or pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor using the compounds or compositions described herein, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) using the compounds and compositions described herein and processes for making compounds described herein and intermediates useful in the preparation of same.