Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders
| Autor: | Dan Shi, Moore Nigel St John, Donald B. Konopacki, Kelly J. Larson, Gary Gintant, Kathy K. Sarris, Peter F. Bousquet, Sean C. Turner, Peng Zhang, Ayome Abibi, Christopher M. Harris, Tegest Kebede, Xiubo Tang, Adrian D. Hobson, John W. Maull, Elizabeth Louise van der Kam, Ana L. Aguirre, Youngjae Kim, Anurupa Shrestha |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Agonist medicine.drug_class Sphingosine-1-phosphate receptor Administration Oral Pharmacology Cell Line Rats Sprague-Dawley Mice Dogs In vivo Drug Discovery Benzene Derivatives medicine Animals Humans Cognitive decline Receptor Mice Inbred BALB C Chemistry Neurodegenerative Diseases In vitro Rats Bioavailability Mice Inbred C57BL Macaca fascicularis Receptors Lysosphingolipid Blood-Brain Barrier Cognitive Aging Molecular Medicine Female Azetidinecarboxylic Acid Function (biology) |
| Zdroj: | Journal of Medicinal Chemistry. 58:9154-9170 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b00928 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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