Discovery of a Novel Orally Active, Selective LPA Receptor Type 1 Antagonist, 4-(4-(2-Isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidin-1-yl)-4-oxobutanoic Acid, with a Distinct Molecular Scaffold.
J Med Chem
; 67(4): 2379-2396, 2024 Feb 22.
Article
in En
| MEDLINE
| ID: mdl-38349223
ABSTRACT
Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 ß-arrestin recruitment-based high-throughput screening campaign, we identified urea 19 as a hit with a LPAR1 IC50 value of 5.0 µM. Hit-to-lead activities revealed that one of the urea nitrogen atoms can be replaced by carbon and establish the corresponding phenylacetic amide as a lead structure for further optimization. Medicinal chemistry efforts led to the discovery of piperidine 18 as a potent and selective LPAR1 antagonist with oral activity in a mouse model of LPA-induced skin vascular leakage. The molecular scaffold of 18 shares no obvious structural similarity with any other LPAR1 antagonist disclosed so far.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Lysophosphatidic Acid
/
Amides
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Switzerland