LPAR1 Antagonist Compounds With Selective, Stable Receptor Inhibition
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Solution Overview
Problem
There is a need for LPA receptor antagonists with desirable selectivity, potency, metabolic stability, or reduced detrimental effects for the treatment and/or prophylaxis of diseases associated with LPA receptors, such as cancer, fibrosis, inflammation, pain, and cardiovascular diseases.
Innovation Solution
Development of compounds that act as inhibitors of Lysophosphatidic Acid Receptor 1 (LPAR1), including specific chemical structures and pharmaceutical compositions for administering these compounds to inhibit LPAR1 activity and treat associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing LPA receptor antagonists are used, then LPAR1 activity can be inhibited, but selectivity, potency, or metabolic stability is insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structure parameters of LPA receptor antagonists. Specifically, the invention changes the core structural framework from prior art compounds (e.g., using different heterocyclic rings, adjusting substituent positions and types) to achieve improved selectivity for LPAR1 over other LPA receptors, enhanced potency with lower IC50 values, and better metabolic stability. The detailed structural modifications including varying R1-R6 substituents and core ring structures represent parameter changes that resolve the contradiction between efficacy and safety.
2Adaptability or versatility
If broader LPA receptor inhibition is achieved, then multiple disease conditions can be treated, but selectivity for specific LPAR1-mediated conditions is reduced
Solution Approach 1:
The patent applies local quality by designing compounds with specific local structural features that target LPAR1 selectively. The invention introduces particular substituent patterns at specific positions (R1-R6) that create localized interactions with LPAR1 binding site residues, enabling selective inhibition of LPAR1 while sparing other LPA receptors (LPAR2-6). This local optimization of molecular structure allows the compound to maintain high selectivity for LPAR1 while still being applicable to multiple LPAR1-mediated diseases including fibrosis, cancer, and inflammatory conditions.
Data Source
AI summary
The present disclosure relates generally to compounds that bind to Lysophosphatidic Acid Receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure 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 LPAR1, including fibrosis and liver diseases such as non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD).