Selective Androgen Receptor Modulators Tissue Selectivity
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Solution Overview
Problem
Current androgen therapies face challenges in minimizing stimulatory effects on the prostate and other untoward effects, such as masculinization and acne, while maintaining muscle growth and other therapeutic benefits.
Innovation Solution
Development of selective androgen receptor modulators (SARMs) that selectively target specific tissues, such as the compound of formula I, which modulates the androgen receptor to mimic the effects of testosterone or dihydrotestosterone without stimulating the prostate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If androgen agonists are used to stimulate muscle growth and bone density, then therapeutic benefits are improved, but prostate stimulation and other untoward effects worsen
Solution Approach 1:
The patent applies local quality by designing SARM compounds with specific molecular structures (formula I and II) that exhibit tissue-selective binding affinity. The compounds are engineered to preferentially bind to androgen receptors in muscle and bone tissues while having reduced affinity for prostate androgen receptors, thereby achieving localized therapeutic effects with minimized systemic side effects
Solution Approach 2:
The patent segments the androgen receptor binding property into tissue-specific interactions. By modifying the molecular structure with specific substituents (R1-R6 groups) and stereochemical configurations, the compounds are divided into variants with different tissue selectivity profiles, allowing optimization for specific therapeutic indications while minimizing unwanted effects in particular organs
2Quantity of substance
If androgen agonists are used to increase muscle mass, then anabolic effects are improved, but side effects like acne and masculinization worsen
Solution Approach 1:
The SARM compounds are designed with specific molecular features that confer selectivity for muscle and bone androgen receptors over sebaceous gland and other tissue receptors. This local quality differentiation allows the compounds to produce anabolic effects in target tissues while minimizing androgenic side effects in other tissues, thereby reducing acne and unwanted masculinization
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters (substituent groups, stereochemistry, molecular weight) to optimize the balance between anabolic efficacy and androgenic side effects. By adjusting these chemical parameters, the compounds achieve enhanced muscle growth with reduced acne and masculinization compared to conventional androgens
3Adaptability or versatility
If selective androgen receptor modulators are designed to target specific tissues, then tissue selectivity is improved, but compound complexity worsens
Solution Approach 1:
The patent achieves tissue selectivity through local quality modifications in the molecular structure, specifically at key positions (R1-R6 substituents and stereochemical centers) that determine receptor binding specificity. These localized structural features provide the necessary tissue selectivity without requiring complete redesign of the entire molecular framework, thus managing complexity while achieving versatility
Data Source
AI summary
This invention provides compounds of formulas H, Ia, H, and or salts thereof, pharmaceutical compositions comprising a compound of formulas H, Ia, H and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, 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) and processes for making compounds of formulas H, Ia, H, and intermediates useful in the preparation of same. (I)