Substituted Condensed Thiophenes Modulate STING Activity
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Solution Overview
Problem
Current treatments for diseases involving modulation of STING, such as autoimmune and infectious diseases, lack effective small molecule compounds that can specifically activate or inhibit STING to regulate type I interferon production, leading to inadequate therapeutic outcomes.
Innovation Solution
Development of a compound of formula I, which modulates STING activity by binding to it, allowing for the regulation of type I interferon production and cytokine induction, thereby treating or preventing diseases associated with STING modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing small molecule compounds are used to modulate STING, then some therapeutic effect is achieved, but the activation or inhibition of STING is insufficient and type I interferon production is not adequately regulated
Solution Approach 1:
The patent modifies the chemical structure of STING modulators by changing molecular parameters - specifically incorporating substituted condensed thiophene core structures with varying substituents at defined positions. This structural parameter change enables enhanced binding affinity and more effective modulation of STING activity, directly resolving the insufficiency of existing compounds in activating or inhibiting STING and regulating type I interferon production.
2Object-affected harmful factors
If STING is activated to treat infectious diseases, then immune response is enhanced, but unwanted side effects and toxicity may occur
Solution Approach 1:
The patent introduces substituents at specific local positions (R1-R6) on the condensed thiophene core structure, creating local chemical variations that fine-tune the compound's binding characteristics. This local quality modification allows selective modulation of STING activity - enhancing immune response where needed while minimizing unwanted side effects and toxicity through precise structural control at specific molecular locations.
Solution Approach 2:
By systematically varying chemical parameters (substituents, their positions, and molecular weights) in the condensed thiophene structure, the patent optimizes the balance between STING activation capability and toxicity profile. This parameter optimization enables effective immune response activation for treating infectious diseases while reducing harmful side effects.
3Reliability
If STING is inhibited to treat autoimmune diseases, then inflammation is reduced, but efficacy in regulating type I interferon production is insufficient
Solution Approach 1:
The patent employs substituted condensed thiophene structures with varied substituents to achieve potent STING inhibition. The specific molecular parameters (substituent types, positions, and configurations) are optimized to ensure strong binding to STING and effective inhibition of type I interferon production, thereby achieving both reliable inflammation control and sufficient interferon regulation for treating autoimmune diseases.
Data Source
AI summary
A compound of formula (I):wherein: R1 is selected from (i) H, (ii) C3-6cycloalkyl, (iii) C3-7heterocyclyl optionally substituted with a group selected from: methyl and ester, and (iv) linear or branched C1-4alkyl optionally substituted with a group selected from: alkoxy, amino, amido, acylamido, acyloxy, alkyl carboxyl ester, alkyl carbamoyl, alkyl carbamoyl ester, phenyl, phosphonate ester, C3-7heterocyclyl optionally substituted with a group selected from methyl and oxo, and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A1 is CRA or N; A2 is CRB or N; A3 is CRC or N; A4 is CRD or N; where no more than two of A1, A2, A3, and A4 may be N; one or two of RA, RB, RC, and RD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and CH2NMe2; the remainder of RA, RB, RC, and RD, (if present) are H; Y is O, NH or CH2; RY is selected from: (RYA) and (RYB).