Heterocyclic FXR Agonists Optimizing Pharmacokinetic Properties
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Solution Overview
Problem
Current FXR modulators face challenges due to undesirable pharmacokinetic properties such as poor bioavailability, short or long half-life, and extensive first-pass metabolism, leading to high failure rates in drug development, primarily attributed to suboptimal physicochemical and ADME parameters.
Innovation Solution
Development of novel compounds that act as agonists or partial agonists of the NR1H4 receptor (FXR) with improved physicochemical and ADME properties, including enhanced bioavailability and half-life, as defined by the general formula (I), which bind to the FXR and are synthesized through specific methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current FXR modulators are used, then FXR binding activity is achieved, but pharmacokinetic properties are poor (low bioavailability, short half-life, extensive first-pass metabolism)
Solution Approach 1:
The patent applies parameter changes by systematically modifying the physicochemical properties of FXR modulators through structural optimization. Specific molecular parameters such as lipophilicity, molecular weight, and solubility are adjusted to achieve optimal pharmacokinetic profiles. The compounds are designed to meet specific parameter ranges that improve bioavailability while maintaining FXR binding affinity, directly resolving the contradiction between achieving FXR activity and poor pharmacokinetic properties.
2Duration of action of moving object
If current FXR modulators are used, then FXR binding activity is achieved, but half-life is suboptimal (short or excessively long)
Solution Approach 1:
The patent optimizes the half-life parameter by adjusting molecular characteristics such as metabolic stability, protein binding affinity, and elimination rate constants. Through systematic structural modifications, the compounds achieve a balanced half-life that maintains therapeutic efficacy without causing accumulation or rapid clearance, directly addressing the contradiction between duration of action and overall pharmacokinetic reliability.
3Reliability
If current FXR modulators are used, then FXR binding activity is achieved, but first-pass metabolism is extensive
Solution Approach 1:
The patent reduces first-pass metabolism by modifying metabolic stability parameters through structural optimization. Specific molecular features are adjusted to decrease susceptibility to hepatic metabolism and intestinal degradation. The compounds are designed with enhanced metabolic stability that reduces the extent of first-pass elimination, thereby improving the fraction of drug reaching systemic circulation and resolving the contradiction between pharmacokinetic reliability and substance loss.
4Quantity of substance
If FXR modulators with improved pharmacokinetic properties are developed, then bioavailability and half-life are enhanced, but compound structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecular optimization process into distinct structural modules and functional domains. Each module addresses specific pharmacokinetic parameters independently, allowing systematic improvement of bioavailability without overwhelming structural complexity. This modular approach enables rational drug design where each structural element contributes to specific PK properties while maintaining overall molecular manageability.
Solution Approach 2:
The patent employs multi-functionality by designing structural features that simultaneously address multiple pharmacokinetic parameters. A single molecular modification may improve both solubility and metabolic stability, or enhance both bioavailability and half-life. This approach reduces the need for numerous separate structural changes, thereby improving pharmacokinetic properties while limiting the increase in overall compound structure complexity.
Data Source
AI summary
The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists or partial agonists of the NR1H4 receptor (FXR). The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds, and to a process for the synthesis of said compounds.