Discovery of A‑971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood–brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris , 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood–brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood–brain barrier such as Alzheimer’s disease or multiple sclerosis.

S1P5是鞘氨醇-1-磷酸（sphingosine-1-phosphate）的5种受体亚型之一，在血脑屏障（blood–brain barrier）内的内皮细胞中高表达，体外模型研究显示其可维持屏障完整性（《Journal of Neuroinflammation》, 2012, 9, 133）。由于缺乏具备合适选择性及类药特性的工具分子，目前学界对S1P5调控的效应仍知之甚少。我们此前曾报道，分子A-971432（Harris等，2010）即本文中的化合物29，可有效逆转大鼠体内的脂质堆积与年龄相关性认知衰退（Van der Kam等，AAIC 2014）。本文中，我们报道了一系列选择性S1P5激动剂的研发过程，最终筛选得到化合物29：该化合物对S1P5具有极高选择性，且在临床前物种中口服给药后，可实现优异的血浆与中枢神经系统（CNS）暴露量。为进一步验证其适用于S1P5生物学的体内研究，我们对化合物29进行了全面表征，包括确认其在大鼠体内S1P1与S1P3功能的药效学试验中的选择性。此外，我们发现化合物29可在体外模型中改善血脑屏障完整性，并逆转小鼠的年龄相关性认知衰退。上述结果表明，S1P5激动疗法是一种创新性策略，有望为脂质代谢失衡和/或血脑屏障受损的神经退行性疾病（如阿尔茨海默病、多发性硬化）带来治疗获益。