Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor

Jonathan Ellery (Lead / Corresponding author), Louise Dickson, Toni Cheung, Loredana Ciuclan, Peter Bunyard, Stephen Mack, William J. Buffham, William Farnaby, Philip Mitchell, Daniel Brown, Richard Isaacs, Matt Barnes

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)8-15
Number of pages8
JournalEuropean Journal of Pharmacology
Volume833
Early online date26 May 2018
DOIs
Publication statusPublished - 15 Aug 2018

Fingerprint

Lysophosphatidic Acid Receptors
Interferometry
Physiological Phenomena
Arrestin
Benzoic Acid
Carboxylic Acids
Fibrosis
Binding Sites
Clinical Trials
Calcium

Keywords

  • Backscattering interferometry
  • Fibrosis
  • G-protein signalling
  • LPA receptor
  • Negative allosteric modulator

Cite this

Ellery, J., Dickson, L., Cheung, T., Ciuclan, L., Bunyard, P., Mack, S., ... Barnes, M. (2018). Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor. European Journal of Pharmacology, 833, 8-15. https://doi.org/10.1016/j.ejphar.2018.05.040
Ellery, Jonathan ; Dickson, Louise ; Cheung, Toni ; Ciuclan, Loredana ; Bunyard, Peter ; Mack, Stephen ; Buffham, William J. ; Farnaby, William ; Mitchell, Philip ; Brown, Daniel ; Isaacs, Richard ; Barnes, Matt. / Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor. In: European Journal of Pharmacology. 2018 ; Vol. 833. pp. 8-15.
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abstract = "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 receptor, Negative allosteric modulator",
author = "Jonathan Ellery and Louise Dickson and Toni Cheung and Loredana Ciuclan and Peter Bunyard and Stephen Mack and Buffham, {William J.} and William Farnaby and Philip Mitchell and Daniel Brown and Richard Isaacs and Matt Barnes",
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Ellery, J, Dickson, L, Cheung, T, Ciuclan, L, Bunyard, P, Mack, S, Buffham, WJ, Farnaby, W, Mitchell, P, Brown, D, Isaacs, R & Barnes, M 2018, 'Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor', European Journal of Pharmacology, vol. 833, pp. 8-15. https://doi.org/10.1016/j.ejphar.2018.05.040

Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor. / Ellery, Jonathan (Lead / Corresponding author); Dickson, Louise; Cheung, Toni; Ciuclan, Loredana; Bunyard, Peter; Mack, Stephen; Buffham, William J.; Farnaby, William; Mitchell, Philip; Brown, Daniel; Isaacs, Richard; Barnes, Matt.

In: European Journal of Pharmacology, Vol. 833, 15.08.2018, p. 8-15.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of compounds acting as negative allosteric modulators of the LPA 1 receptor

AU - Ellery, Jonathan

AU - Dickson, Louise

AU - Cheung, Toni

AU - Ciuclan, Loredana

AU - Bunyard, Peter

AU - Mack, Stephen

AU - Buffham, William J.

AU - Farnaby, William

AU - Mitchell, Philip

AU - Brown, Daniel

AU - Isaacs, Richard

AU - Barnes, Matt

N1 - This work was supported by Takeda Cambridge Ltd.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

KW - Backscattering interferometry

KW - Fibrosis

KW - G-protein signalling

KW - LPA receptor

KW - Negative allosteric modulator

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