Purity: > 98%
A‑971432(cas 1240308-45-5) is a potent, orally bioavailable, selective Sphingosine-1-Phosphate Receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders. A‑971432 is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. A‑971432 improves blood−brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. S1P5 agonism is an innovative approach with potentialbenefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood−brain barrier such as Alzheimer’s disease or multiple sclerosis.
1. J Med Chem. 2015 Dec 10;58(23):9154-70. doi: 10.1021/acs.jmedchem.5b00928. Epub
2015 Nov 23.
Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate
Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative
Hobson AD(1), Harris CM(1), van der Kam EL(2), Turner SC(2), Abibi A(1), Aguirre
AL(3), Bousquet P(1), Kebede T(1), Konopacki DB(1), Gintant G(3), Kim Y(1),
Larson K(3), Maull JW(1), Moore NS(1), Shi D(1), Shrestha A(3), Tang X(4), Zhang
P(4), Sarris KK(3).
(1)AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts
01605, United States. (2)AbbVie Deutschland GmbH & Co KG , Knollstrasse 50, 67061
Ludwigshafen, Germany. (3)AbbVie, Inc. , 1 North Waukegan Road, North Chicago,
Illinois 60064, United States. (4)Shanghai ChemPartner Co. Ltd. , Building 10,
998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
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.
PMID: 26509640 [Indexed for MEDLINE]