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, 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.
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Adrian D
AD
Hobson
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Christopher M
CM
Harris
AbbVie Deutschland GmbH & Co KG , Knollstrasse 50, 67061 Ludwigshafen, Germany.
Elizabeth L
EL
van der Kam
AbbVie Deutschland GmbH & Co KG , Knollstrasse 50, 67061 Ludwigshafen, Germany.
Sean C
SC
Turner
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Ayome
A
Abibi
AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Ana L
AL
Aguirre
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Peter
P
Bousquet
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Tegest
T
Kebede
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Donald B
DB
Konopacki
AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Gary
G
Gintant
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Youngjae
Y
Kim
AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Kelly
K
Larson
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
John W
JW
Maull
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Nigel S
NS
Moore
AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Dan
D
Shi
AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Anurupa
A
Shrestha
Shanghai ChemPartner Co. Ltd. , Building 10, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
Xiubo
X
Tang
Shanghai ChemPartner Co. Ltd. , Building 10, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
Peng
P
Zhang
AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Kathy K
KK
Sarris
D000284:Administration, Oral; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D000066492:Cognitive Aging; D004285:Dogs; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism
D001555:Benzene Derivatives; D049349:Receptors, Lysosphingolipid; C538898:azetidine-2,3-dicarboxylic acid; D001383:Azetidinecarboxylic Acid