18-Methyl-19-Nor-Androst-Spiroether Receptor Selectivity
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Solution Overview
Problem
Current gestagen compounds like drospirenone have a dissociated profile regarding binding to progesterone and mineralocorticoid receptors, with low affinity for the progesterone receptor and high affinity for the mineralocorticoid receptor, which affects their efficacy and side effects.
Innovation Solution
Development of 18-methyl-15β,16β-methylene-19-nor-20-spirox-4-en-3-one compounds with a specific structural formula that enhances binding to the progesterone receptor while reducing binding to the mineralocorticoid receptor, thereby improving gestagen activity and minimizing antimineralcorticoid effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If drospirenone is used as a gestagen compound, then antimineralcorticoid effect is achieved, but binding affinity to progesterone receptor remains low
Solution Approach 1:
The patent modifies the chemical structure of drospirenone by introducing a 19-nor group and a 20-spiroxane ring system with specific stereochemistry (15β,16β-methylene). These structural parameter changes fundamentally alter the receptor binding profile, enabling strong affinity for the progesterone receptor while reducing affinity for the mineralocorticoid receptor, thus resolving the dissociated profile problem
Solution Approach 2:
The invention creates a hybrid molecular structure combining elements of traditional gestagens with spiroxane ring systems. This composite molecular architecture integrates the gestagenic activity of progesterone analogs with the structural features of spiro compounds, achieving both strong progesterone receptor binding and reduced mineralocorticoid receptor interaction
2Reliability
If drospirenone binds strongly to mineralocorticoid receptor, then antimineralcorticoid effect is produced, but gestagen activity is reduced
Solution Approach 1:
The patent introduces specific local structural features at key positions of the molecule: the 19-nor substitution and the 20-spiroxane ring with defined stereochemistry. These localized structural modifications selectively enhance interaction with the progesterone receptor binding site while minimizing interaction with the mineralocorticoid receptor, achieving differentiated receptor selectivity
Data Source
AI summary
The invention relates to novel 18-methyl-19-nor-androst-4-en-17,17- spiroether of general formula (I), where Z = O, two H, =NOR or =NNHSO2R, R = H, or straight or branched chain C1-4 or C3-4alkyl, R4 = H, halogen, or CF3 and R6 and/or R7 are a- or ß-positioned and R6 and R7 independently = H or straight or branched chain C1-4 or C3-4alkyl or a straight or branched chain C2-4 or C3-4alkylene or a saturated C3-5 cycloalkyl, or together form a methylene group or a double bond. The novel compounds have gestagenic and antimineralcorticoid action.