1240308-45-5

Basic information

• Product Name: 1-(4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3-carboxylic acid
• Synonyms: 1-(4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3-carboxylic acid
• CAS NO: 1240308-45-5
• Molecular Weight: 366.244
• Mol File: 1240308-45-5.mol
• Article Data: 2

Chemical Properties

• CAS DataBase Reference: 1-(4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3-carboxylic acid(1240308-45-5)
• EPA Substance Registry System: 1-(4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3-carboxylic acid(1240308-45-5)

Safety Data

• Hazardous Substances Data: 1240308-45-5(Hazardous Substances Data)

Usage

Uses

A 971432 is used in the preparation of benzylazetidinecarboxylate derivatives as agonists and antagonists of the S1P5 receptor.

Biochem/physiol Actions

A-971432 is an orally bioavailable, non-clastogenic, azetidinecarboxylate compound that acts as a highly potent and selective sphingosine-1-phosphate receptor 5 agonist (IC50?= 6 nM/S1P5, 362 nM/S1P1 and >10 μM/S1P3 in a radio-ligand binding assay) without affect the activity of 129 protein kinases (IC50?>10 μM). A-971432 is shown to enhance blood-brain barrier integrity and reverse lipid accumulation and age-related cognitive decline in mice in vivo with good pharmacokinetics (t1/2??= 5.7 h; Cmax?= 2,500 ng/ml; AUC = 35,000 ng.h/ml at 10 mg/kg, p.o. in CD1 mice). Likewise, oral gavage showed good plasma exposure and no sign of lymphopenia in rats (10, 30, and 100 mg/kg.

Upstream product

• 66742-56-1 4-(3,4-dichlorobenzyloxy)-benzaldehyde 
• 36476-78-5 3-azetidinecarboxylic acid 

Relevant articles and documents

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 et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., 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.