CD38 Inhibitor Compounds With N-Heteroaryl PK Improvement
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Solution Overview
Problem
Existing CD38 inhibitors face challenges in drug-drug interaction (DDI) and have suboptimal pharmacokinetic profiles, limiting their efficacy and safety in treating diseases mediated by CD38, such as neurodegenerative diseases, cancer, and autoimmune diseases.
Innovation Solution
Development of novel compounds with a phenyl group having one or two carbon atoms replaced with N, enhancing CD38 inhibition activity, improving solubility, and extending half-life, thereby reducing drug-drug interactions and increasing in vivo exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CD38 inhibitors are used, then CD38 inhibition activity is achieved, but drug-drug interaction (DDI) occurs and pharmacokinetic profiles are suboptimal
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of CD38 inhibitors, specifically replacing cycloalkyl groups with phenyl groups having one or two carbon atoms replaced with N (creating pyridinyl or pyrimidinyl structures). This structural parameter change results in improved pharmacokinetic profiles, reduced CYP inhibition, and decreased drug-drug interactions while maintaining CD38 inhibition activity
Solution Approach 2:
The patent creates composite molecular structures by combining specific substituents (A1, A2, A3 groups) with the core CD38 inhibitor scaffold. The composite structure includes halogen or heterocyclic groups at A1, nitrogen-containing aromatic rings at A2 and A3, creating a multi-component molecular architecture that achieves both therapeutic efficacy and improved safety profile
2Reliability
If existing CD38 inhibitors are used, then therapeutic effect is achieved, but solubility and pharmacokinetic profiles are suboptimal
Solution Approach 1:
The patent modifies molecular parameters by introducing nitrogen atoms into the aromatic rings (creating pyridinyl or pyrimidinyl groups instead of simple phenyl groups). This parameter change enhances the polarity and hydrogen-bonding capability of the molecules, resulting in improved solubility and pharmacokinetic properties including longer half-life and higher in vivo exposure
3Reliability
If existing CD38 inhibitors are used, then disease treatment is achieved, but half-life is short and in vivo exposure is limited
Solution Approach 1:
The patent designs composite molecular structures with specific substituent patterns (halogen groups, nitrogen-containing aromatic rings, and various alkyl/alkoxy substituents) that enhance metabolic stability. These composite structures demonstrate slower in vivo metabolism, leading to extended half-life and increased in vivo exposure, thereby improving therapeutic efficacy
Data Source
AI summary
The present invention provides compounds of Formula I which can be used as CD38 inhibitors; methods for the production of the compounds of the invention; pharmaceutical compositions comprising the compounds of the invention; as well as uses and methods for treating a disease mediated by CD38 by administering the compounds of the invention.