Identification of compounds acting as negative allosteric modulators of the LPA1 receptor

Eur J Pharmacol. 2018 Aug 15;833:8-15. doi: 10.1016/j.ejphar.2018.05.040. Epub 2018 May 26.


The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4-({(Cyclopropylmethyl)[4-(2-fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK-615) with BMS-986202 and SAR-100842. Back-scattering interferometry (BSI) was used to show that the apparent affinity of TAK-615 was enhanced in the presence of LPA. The binding signal for BMS-986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR-100842 was also enhanced in the presence of LPA. Only BMS-986202 was able to fully inhibit the response to LPA in calcium mobilisation, β-arrestin, cAMP, GTPγS and RhoA functional assays. TAK-615 and SAR-100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK-615 is not competitive with either SAR-100842 or BMS-986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK-615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR-100842 also behaves like a NAM. BMS-986202 on the other hand behaves like an orthosteric antagonist.

Keywords: Backscattering interferometry; Fibrosis; G-protein signalling; LPA(1) receptor; Negative allosteric modulator.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology*
  • Indenes / chemistry
  • Indenes / pharmacology*
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Rats
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / metabolism*


  • BMS-986202
  • Benzamides
  • Benzoates
  • Cyclopropanes
  • Indenes
  • Oxazoles
  • Receptors, Lysophosphatidic Acid
  • SAR-100842
  • TAK-615
  • Cyclic AMP
  • Calcium