2. Academic Validation
  3. 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

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. 2024 Feb 22;67(4):2379-2396. doi: 10.1021/acs.jmedchem.3c01826.
Cyrille Lescop 1,  Christine Brotschi 1,  Jodi T Williams 1,  Christoph P Sager 1,  Magdalena Birker 2,  Keith Morrison 3,  Sylvie Froidevaux 3,  Stéphane Delahaye 4,  Oliver Nayler 2,  Martin H Bolli 1
Affiliations

Affiliations

  • 1 DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 2 DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 3 DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 4 Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
PMID: 38349223 DOI: 10.1021/acs.jmedchem.3c01826
Abstract

Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 β-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.

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