Fused Ring Urea Compounds for NAMPT Activation
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Solution Overview
Problem
Current compounds do not effectively activate nicotinamide phosphoribosyltransferase (NAMPT), which is crucial for maintaining intracellular energy homeostasis and preventing cell death.
Innovation Solution
Development of fused ring compounds with a specific urea structure that act as potent NAMPT activators, enhancing NAMPT activity and promoting energy metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional compounds are used, then NAMPT activation is insufficient, but the invention introduces fused ring compounds with specific urea structure to achieve potent NAMPT activation
Solution Approach 1:
The compound structure is segmented into distinct functional components: a bicyclic ring system (ring B) providing structural framework, a urea group (NH-CO-NH) serving as the active pharmacological moiety, and various substituents (R1, R2, R3 groups) that modulate activity. This segmentation allows optimization of each component independently to achieve potent NAMPT activation.
Solution Approach 2:
The invention systematically varies chemical parameters including substituent types on the bicyclic ring, the urea group connectivity, and side chain configurations to optimize NAMPT binding affinity and catalytic activity. These parameter changes transform conventional compounds into potent activators with enhanced efficacy.
2Quantity of substance
If NAMPT activity is increased to improve energy homeostasis, then NAD+ levels increase, but the patent addresses diseases mediated by NAMPT activity requiring precise control
Solution Approach 1:
The compounds provide feedback control by binding to NAMPT and modulating its catalytic activity toward NMN synthesis. This regulated feedback mechanism increases NAD+ levels while preventing excessive NAMPT activity that could mediate harmful disease processes, achieving therapeutic balance.
Solution Approach 2:
The invention changes the kinetic parameters of NAMPT by introducing fused ring compounds with specific urea structures that alter the enzyme's catalytic rate and substrate affinity. This enables precise control over NAD+ synthesis rates, increasing NAD+ levels without triggering disease-mediated pathways.
Data Source
AI summary
The present invention relates to a novel fused ring compound having urea structure that exhibits excellent NAMPT activating effect, and a method using the same for treating/preventing metabolic disorder, cardiovascular and kidney disease, mitochondrial disease, neurodegenerative disease, ocular disease, and muscle wasting disorder.The present invention provides a compound represented by following formula (I) or a pharmacologically acceptable salt:wherein A, B, R1, R2 and R3 represent the same meanings as in the claims.