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.

中文翻译：

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鉴定充当LPA1受体的负变构调节剂的化合物。

溶血磷脂酸1受体（LPA1受体）已与各种治疗不良的纤维化病况的发生和发展有关。已描述为LPA1受体拮抗剂的几种化合物已进入临床试验：1-（4- {4- [3-甲基-4-（{[（（R）-1-苯基乙氧基]羰基}氨基）-氨基）-1,2 -恶唑-5-基]苯基}苯基}环丙烷-1-甲酸（BMS-986202）和2- {4-甲氧基-3- [2-（3-（甲基苯基）乙氧基]苯甲酰胺基）-2,3-二氢-1H-茚-2-羧酸（SAR-100842）。我们认为，由于LPA1受体功能涉及许多正常的生理过程，因此抑制与纤维化相关的特定信号通路可能在治疗上是有利的。我们比较了新型化合物的结合和功能作用。这组实验产生的结果表明TAK-615充当LPA1受体的负变构调节剂（NAM）。令人惊讶的是，我们发现SAR-100842的行为也像NAM。另一方面，BMS-986202的行为类似于正构拮抗剂。