Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists,Journal of Medicinal Chemistry

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Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-26 , DOI: 10.1021/acs.jmedchem.3c00951
Pinqi Wang _{1,

2} , Arun Raja _{1,

2} , Vincent B Luscombe ₃ , Carole J R Bataille _{1,

2} , Daniel Lucy _{1,

3} , Vanessa V Rogga ₁ , David R Greaves ₃ , Angela J Russell _{1,

2}

Affiliation

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via G_αi/cAMP and β-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure–activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signaling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on β-arrestin recruitment up to 80 μM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.

中文翻译：

开发高效、G 蛋白途径偏向、选择性、口服生物可利用的 GPR84 激动剂

孤儿 G 蛋白偶联受体 84 (GPR84) 是一种与癌症、炎症和纤维化疾病有关的受体。我们已报道 DL-175 作为 GPR84 的偏向激动剂，通过 G _αi /cAMP 和 β-arrestin 显示差异信号传导，但会快速代谢。在此，我们描述了通过系统结构-活性关系（SAR）分析对 DL-175 的优化。这表明萘基团的取代提高了代谢稳定性，并且向吡啶N-氧化物基团添加5-羟基取代基，产生化合物68 (OX04528)和69 (OX04529)，将cAMP信号传导的效力增强了3个数量级量级至低皮摩尔值。两种化合物在浓度高达 80 μM 时均未显示出对 β-抑制蛋白募集的可检测到的影响。因此，新的 GPR84 激动剂68和69显示出优异的效力、高 G 蛋白信号传导偏差和适当的体内药代动力学特征，这将允许研究 GPR84 偏差激动剂的体内活性。

更新日期：2023-12-26

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