Pyrazolone Compounds Inhibit CD80/CD28 Interaction
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Solution Overview
Problem
Current treatments for medical conditions involving immunomodulation, such as rheumatoid arthritis and multiple sclerosis, lack effective compounds that can inhibit the CD80/CD28 interaction, a crucial step in T-cell activation, which is essential for controlling immune responses.
Innovation Solution
Development of pyrazolone compounds that act as CD80 antagonists, inhibiting the interaction between CD80 and CD28, thereby modulating the immune response, and their use in pharmaceutical compositions for treating various autoimmune and inflammatory conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for autoimmune conditions, then existing therapeutic options are available, but effective inhibition of CD80/CD28 interaction is lacking
Solution Approach 1:
The invention segments the immune activation pathway by specifically targeting and inhibiting the CD80/CD28 interaction, separating this critical co-stimulatory step from other immune response mechanisms. This allows selective modulation of T-cell activation without affecting other immune functions.
Solution Approach 2:
The pyrazolone compounds act as intermediary molecules that bind to CD80 and prevent its interaction with CD28. These small molecule antagonists serve as chemical mediators that disrupt the protein-protein interaction between CD80 and CD28, thereby blocking the co-stimulatory signal required for full T-cell activation.
2Reliability
If T-cell activation is enhanced, then immune response is strengthened, but autoimmune conditions are exacerbated
Solution Approach 1:
The pyrazolone compounds apply preliminary anti-action by preemptively blocking the CD80/CD28 interaction before full T-cell activation can occur. By inhibiting this co-stimulatory signal in advance, the compounds prevent the harmful autoimmune response from being triggered while allowing the immune system to maintain its ability to respond to genuine threats.
Solution Approach 2:
The invention changes the parameter of T-cell activation by selectively reducing the co-stimulatory signal strength through CD80/CD28 inhibition. This parameter change shifts the immune response from an overactivated state (causing autoimmunity) to a regulated state, without completely suppressing immune function.
Data Source
AI summary
Compounds of formula (IA) or (IB) are inhibitors of CD80 and useful in immunomodulation therapy: wherein Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms; R1 and R2 independently represent H, or C1-C6 alkyl; R3 represents H; F; CI; Br, —NO2; —CN; C1-C6 alkyl optionally substituted by F or CI; or C1-C6 alkoxy optionally substituted by F; R4 represents a carboxylic acid group (—COOH) or an ester thereof, or —C(═O)NR6R7, —NR7C(═O)R6, —NR7C(═O)OR6, —NHC(═O)NR7R6 or —NHC(═S)NR7R6 wherein R6 represents H, or a radical of formula -(Alk)m-Q wherein m is 0 or 1, Alk is an optionally substituted divalent straight or branched C1-C12 alkylene, or C2-C12 alkenylene, or C2-C12 alkynylene radical or a divalent C3-C12 carbocyclic radical, any of which radicals may be interrupted by one or more —O—, —S— or —N(R8)— radicals wherein R8 represents H or C1-C4 alkyl, C3-C4 alkenyl, C3-C4 alkynyl, or C3-C6 cycloalkyl, and Q represents H; —CF3; —OH; —SH; —NR8R8 wherein each R8 may be the same or different, or form a ring when taken together with the nitrogen to which they are attached; an ester group; or an optionally substituted aryl, aryloxy, cycloalkyl, cycloalkenyl or heterocyclic group; and R7 represents H or C1-C6 alkyl; or when taken together with the atom or atoms to which they are attached R6 and R7 form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms; and X represents a bond or a divalent radical of formula -(Z)n-(Alk)- or -(Alk)-(Z)n- wherein Z represents —O—, —S— or —NH—, Alk is as defined in relation to R6 and n is 0 or 1.