Selective Glucocorticoid Receptor Modulators for Inflammatory Disease
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Solution Overview
Problem
Current glucocorticoid receptor modulators have limited utility due to serious side effects and inability to selectively modulate downstream signaling, necessitating the development of selective glucocorticoid receptor modulators (SGRMs) with reduced side effects for treating inflammatory-related conditions.
Innovation Solution
Development of novel compounds represented by Formula (I) and their pharmaceutical compositions, which act as selective glucocorticoid receptor modulators, influencing various bodily systems and providing therapeutic benefits with reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoid receptor agonists are used to treat inflammatory conditions, then anti-inflammatory efficacy is improved, but serious side effects such as osteoporosis, diabetes, skin thinning, and fluid homeostasis disturbances occur
Solution Approach 1:
The patent segments the glucocorticoid receptor signaling pathway into distinct functional domains, designing compounds that selectively activate anti-inflammatory pathways while avoiding pro-inflammatory and metabolic pathways. This is achieved through specific molecular structures (Formulas I and II) that target particular receptor conformations or downstream signaling cascades, thereby separating therapeutic effects from adverse effects.
Solution Approach 2:
The invention applies local quality by creating glucocorticoid modulators with tissue-specific or pathway-specific selectivity. The compounds in Formulas I and II are designed to exhibit different binding characteristics to various steroid receptors (glucocorticoid, mineralocorticoid, androgen, estrogen, progesterone receptors), allowing selective modulation of the glucocorticoid receptor while sparing other receptor systems that mediate side effects.
2Adaptability or versatility
If traditional glucocorticoid receptor modulators are used, then broad anti-inflammatory coverage is achieved, but selectivity for downstream signaling pathways is lost
Solution Approach 1:
The patent employs parameter changes by systematically varying molecular structures (substituents R1-R6, ring systems A'-C) to fine-tune the selectivity profile of glucocorticoid modulators. These structural parameters determine binding affinity and selectivity for the glucocorticoid receptor versus other steroid receptors, as well as selectivity for different downstream signaling pathways, enabling precise control over therapeutic versus side effect profiles.
Data Source
AI summary
The invention provides a compound of Formula (I)pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.