Phthalazine Compounds Modulating p38 Kinase for Inflammation
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Solution Overview
Problem
Current approaches to addressing TNF-α, IL-1β, and IL-6 mediated diseases, such as inflammation and pain, are limited in efficacy and specificity, particularly in modulating the activity of the p38 kinase enzyme for therapeutic benefits.
Innovation Solution
Development of a new class of compounds defined by Formula I, which modulate the activity of the p38 kinase enzyme, allowing for the prophylaxis and treatment of TNF-α, IL-1β, IL-6, and IL-8 mediated diseases, including inflammation, pain, and diabetes, through pharmaceutical compositions and intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current approaches to modulating p38 kinase activity are used, then some therapeutic effect is achieved, but efficacy and specificity are limited
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of p38 kinase modulators through various substituents (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100) to optimize both binding affinity and selectivity for the p38 kinase enzyme, thereby improving therapeutic efficacy while enhancing specificity
Solution Approach 2:
The patent applies local quality by introducing specific functional groups and structural features at particular positions on the p38 kinase binding interface, allowing for differentiated interactions with the enzyme that enhance both potency and selectivity for the p38 isoform over other kinases
2Reliability
If p38 kinase activity is modulated to treat inflammatory diseases, then therapeutic benefits are achieved, but off-target effects may occur
Solution Approach 1:
The patent uses parameter changes by systematically varying molecular properties such as lipophilicity, molecular weight, and functional group composition to optimize the drug's selectivity for p38 kinase while minimizing interactions with other kinases, thereby reducing off-target effects
Solution Approach 2:
The patent incorporates feedback mechanisms through iterative optimization of compound structures based on biochemical assays and cellular models that measure both p38 kinase inhibition and selectivity, allowing for refinement of compounds to maximize therapeutic benefit while minimizing off-target effects
Data Source
AI summary
The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I wherein A1, A2, B, R1, R2, R3 and R4 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.