Phenyl Urea NAMPT Modulators for NAD+ Biosynthesis
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Solution Overview
Problem
Current methods fail to effectively boost NAD+ levels in cells, which are crucial for addressing a wide range of diseases and conditions including cardiac diseases, chemotherapy-induced tissue damage, renal diseases, and neurological disorders, as they rely on inefficient pathways for NAD synthesis.
Innovation Solution
Development of phenyl urea compounds that act as modulators or activators of nicotinamide phosphoribosyltransferase (NAMPT), enhancing NAD+ biosynthesis by increasing the rate of NAMPT catalysis, thereby addressing the decline in cellular NAD+ levels associated with various diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current methods are used to boost NAD+ levels, then NAD+ synthesis is attempted, but the synthesis pathway is inefficient and fails to effectively increase NAD+ levels
Solution Approach 1:
The patent changes the biochemical parameter of NAD+ synthesis by introducing alternative pathways (de novo synthesis from tryptophan, Preiss-Handler pathway from nicotinic acid) to bypass the rate-limiting salvage pathway. This parameter change in the metabolic route enables effective NAD+ production by utilizing different enzymatic routes that are not constrained by NAMPT activity limitations.
2Productivity
If NAMPT catalysis rate is increased, then NAD+ biosynthesis is enhanced, but this requires developing new compound modulators which increases development complexity
Solution Approach 1:
The patent uses phenyl urea compounds as intermediary substances that mediate between the existing NAMPT enzyme and the desired increased NAD+ production. These compounds act as allosteric modulators or activators that bind to NAMPT and enhance its catalytic activity without requiring direct genetic modification or complex enzymatic engineering, thus simplifying the overall approach.
Solution Approach 2:
The patent changes the kinetic parameters of NAMPT enzyme by introducing small molecule modulators that alter enzyme-substrate binding affinity or catalytic turnover rate. This parameter modification allows enhancement of NAD+ biosynthesis through biochemical regulation rather than complex structural engineering of the enzyme itself.
3Reliability
If cellular NAD+ levels are increased, then disease severity is reduced, but current methods are insufficient to achieve effective NAD+ level increases
Solution Approach 1:
The patent employs preliminary action by administering NAMPT modulators or NAD+ precursors before disease progression or in early stages to proactively maintain or boost NAD+ levels. This preventive approach ensures adequate NAD+ availability is established in advance to counteract the metabolic demands and stress conditions that arise during disease states.
Solution Approach 2:
The patent introduces small molecule intermediaries (NAMPT activators, NAD+ precursors like nicotinic acid or tryptophan) that serve as mediators to bridge the gap between current NAD+ production capacity and the higher levels needed for effective disease treatment. These intermediaries facilitate the transition to therapeutic NAD+ levels through enhanced salvage pathway activity or alternative synthesis routes.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The phenyl urea compounds effectively increase NAD+ levels, providing a therapeutic strategy for a broad spectrum of diseases by enhancing NAD+ biosynthesis, thereby improving cellular metabolism and reducing disease severity.
Implementation Method 1
enhancing NAD+ biosynthesis by increasing the rate of NAMPT catalysis
Data Source
AI summary
Provided are compounds of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and p are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (II), or a pharmaceutically acceptable salt thereof.