RESUMEN
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.
Asunto(s)
Ácido Azetidinocarboxílico/análogos & derivados , Derivados del Benceno/química , Derivados del Benceno/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Ácido Azetidinocarboxílico/administración & dosificación , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Ácido Azetidinocarboxílico/farmacología , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacocinética , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Línea Celular , Envejecimiento Cognitivo , Perros , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismoRESUMEN
The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.