1,4-Dihydropyridine Derivatives for Selective Hsp Modulation
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Solution Overview
Problem
Current therapies for neurodegenerative diseases, cancer, metabolic syndromes, and other pathophysiological conditions often induce unwanted side effects due to non-specific stress responses, and there is a need for compounds that can selectively modulate heat shock protein (Hsp) activity without affecting healthy cells.
Innovation Solution
Development of specific 1,4-dihydropyridine derivatives that exhibit selective Hsp co-modulating activity, potentiating or inhibiting stress responses only in diseased tissues, thereby reducing side effects in healthy tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to treat pathophysiological conditions, then therapeutic effect is achieved, but unwanted side effects occur due to non-specific stress responses
Solution Approach 1:
The compound exhibits selective Hsp co-modulating activity that creates different effects in different cellular contexts: in stressed/diseased cells it potentiates Hsp response therapeutically, while in unstressed/healthy cells it has no effect. This local differentiation of action resolves the contradiction between achieving therapeutic effect and avoiding side effects.
Solution Approach 2:
The compound changes the parameter of Hsp protein expression levels in a conditional manner: it increases Hsp levels in cells already under stress (diseased tissues) while maintaining normal Hsp levels in healthy cells. This parameter change based on cellular state resolves the contradiction by providing therapeutic benefit only where needed.
2Reliability
If compounds modulate Hsp activity broadly, then therapeutic benefit is achieved, but side effects in healthy cells occur
Solution Approach 1:
The compound requires pre-existing cellular stress as a prerequisite condition before it can exert its Hsp-modulating effect. Healthy cells without stress do not activate the compound's mechanism, while diseased cells with existing stress respond therapeutically. This preliminary condition requirement resolves the contradiction by preventing effects in healthy cells.
Solution Approach 2:
The compound's activity is segmented into two distinct cellular populations: stressed cells (diseased tissues) where it exerts therapeutic Hsp-modulating activity, and unstressed cells (healthy tissues) where it remains inactive. This segmentation resolves the contradiction by limiting therapeutic action to only the population that needs it.
3Object-affected harmful factors
If selective Hsp co-modulating compounds are developed, then side effects are reduced, but development complexity increases
Solution Approach 1:
The compound utilizes the cell's own stress state as the triggering condition for its activity. Rather than requiring complex external controls or delivery systems, the compound's selective activation is self-regulated by the cellular environment itself (presence or absence of stress). This self-service mechanism resolves the contradiction by achieving selectivity without proportionate increases in development complexity.
Data Source
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AI summary
The invention provides 1,4-dihydropyridine derivatives of formula (I) wherein R1 is optionally substituted C6-24aryl group or 5 to 6 membered heteroaryl group comprising 1 to 3 nitrogen atoms or other heteroatoms like oxygen and sulphur, and combinations thereof; R2 and R3 are independently hydrogen or C1-6alkyl group; R4 and R5 are independently hydrogen, C1-6alkyl group optionally substituted with amino, mono-or di(C1-6alkyl)amino, or with 5 to 24 membered optionally fused heterocyclic ring attached by nitrogen and optionally comprising additional 1 to 3 N, O, S heteroatoms and optionally substituted with C1-6alkyl group or C1-6 alkoxy group; R6 is C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or arylC1-6alkyl group; and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixture of enantiomers and combination thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters and prodrugs thereof for use in the therapeutic or prophylactic treatment of a disorder mediated by heat shock proteins.