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

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• 作者：Adrian D. Hobson ; Christopher M. Harris ; Elizabeth L. van der Kam ; Sean C. Turner ; Ayome Abibi ; Ana L. Aguirre ; Peter Bousquet ; Tegest Kebede ; Donald B. Konopacki ; Gary Gintant ; Youngjae Kim ; Kelly Larson ; John W. Maull ; Nigel S. Moore ; Dan Shi ; Anurupa Shrestha ; Xiubo Tang ; Peng Zhang ; Kathy K. Sarris
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9154-9170
• 全文大小：640K
• ISSN：1520-4804

文摘

S1P₅ is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood鈥揵rain barrier, where it maintains barrier integrity in in vitro models ( J. Neuroinflamm.www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve"> 2012www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, 9www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, 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 (www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" person-group-type="allauthors">Harris,www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve"> 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" person-group-type="author">Van der Kam, , www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">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鈥揵rain 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鈥揵rain barrier such as Alzheimer鈥檚 disease or multiple sclerosis.