Lactam Compounds as Factor Xa Inhibitors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current factor Xa inhibitors are not efficacious enough for treating thromboembolic disorders, lacking specificity and improved pharmacological characteristics such as solubility, dosing requirements, and reduced side effects, and there is a need for new compounds with enhanced selectivity and manufacturing feasibility.
Innovation Solution
Development of novel lactam-containing compounds and their derivatives that act as specific factor Xa inhibitors, formulated into pharmaceutical compositions for effective treatment of thromboembolic disorders, with improved pharmacological properties and manufacturing ease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current factor Xa inhibitors are used, then thromboembolic disorders can be treated, but the efficacy is insufficient and selectivity is poor
Solution Approach 1:
The patent applies local quality by designing a molecule with distinct functional regions: a warhead group for specific covalent bonding to factor Xa, a heterobicyclic group for binding to the S1' pocket, and a basic group for interacting with the active site. This regional differentiation enables both high efficacy through targeted inhibition and high selectivity by matching specific molecular features to the factor Xa active site geometry, resolving the contradiction between reliability and adaptability.
Solution Approach 2:
The invention uses composite molecular structure combining multiple functional groups (warhead, heterobicyclic, basic groups) into a single inhibitor molecule. This composite approach integrates different binding interactions (covalent bonding, hydrophobic interactions, electrostatic interactions) to achieve superior efficacy and selectivity simultaneously, overcoming the limitations of simpler inhibitor structures.
2Reliability
If current factor Xa inhibitors are used, then blood coagulation can be inhibited, but solubility and pharmacokinetic properties are poor
Solution Approach 1:
The patent employs parameter changes by systematically varying the heterobicyclic group structure, basic group type, and substituent patterns to optimize the balance between inhibitory activity and solubility. By adjusting molecular weight, polarity, and hydrogen bonding capacity through different group selections, the invention achieves improved pharmacokinetic properties while maintaining potent factor Xa inhibition, resolving the contradiction between reliability and ease of manufacture.
3Reliability
If current factor Xa inhibitors are used, then thrombin generation can be blocked, but dosing requirements are high and side effects increase
Solution Approach 1:
The invention applies the taking out principle by extracting and optimizing the essential pharmacophore elements needed for factor Xa inhibition while removing unnecessary molecular bulk. The streamlined structure with focused functional groups (warhead, heterobicyclic, basic groups) achieves high potency at lower doses, reducing the quantity of substance required and minimizing off-target effects, thus resolving the contradiction between reliability and quantity of substance.
Data Source
AI summary
The present application describes lactam-containing compounds and derivatives thereof of Formula I: or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.