A-971432 Explained

A-971432 is an orally bioavailable selective agonist of sphingosine-1-phosphate receptor 5 (S1PR5) discovered at AbbVie.^[1] It was discovered using high-throughput chemistry.^[2] S1P5 agonists have been proposed as an innovative mechanism for the treatment of neurodegenerative disorders such as Alzheimer's disease and lysosomal storage disorders such as Niemann–Pick disease.^[3] Stimulation of S1PR5 with A-971432 has been shown to preserve blood-brain barrier integrity and exert a therapeutic effect in an animal model of Huntington's disease.^[4]

Further reading

• Roberts E, Guerrero M, Urbano M, Rosen H . Sphingosine 1-phosphate receptor agonists: a patent review (2010-2012) . Expert Opin Ther Pat . Jul 2013 . 23541049 . 10.1517/13543776.2013.783022 . 23 . 7 . 817–41. 24421259 .

Notes and References

1. WO . 2010093704 . application . Preparation of 1-benzylazetidine-3-carboxylic acid derivatives as agonists and antagonists of the S1P5 receptor . 2010-08-19 . 2009-02-10 . AbbVie .
2. Hobson AD, Harris CM, van der Kam EL, Turner SC, Abibi A, Aguirre AL, Bousquet P, Kebede T, Konopacki DB, Gintant G, Kim Y, Larson K, Maull JW, Moore NS, Shi D, Shrestha A, Tang X, Zhang P, Sarris KK . Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders . Journal of Medicinal Chemistry . Nov 2015 . 26509640 . 10.1021/acs.jmedchem.5b00928 . 58 . 23 . 9154–70.
3. Van der Kam E, Turner S, van Bergeij J, Mueller R, Mezler M, Bespalov A, Hobson A, Harris CM, Rendenbach-Mueller B, Schoemaker H . The use of selective sphingosine-1-phosphate receptor 5 agonists for the treatment of neurodegenerative disorders such as alzheimer's disease and lysosomal storage diseases such as niemann-pick c disease . Alzheimer's & Dementia . Jun 2014 . 10.1016/j.jalz.2014.07.153 . 10 . 4 . P281. 54386805 .
4. Di Pardo A, Castaldo S, Amico E, Pepe G, Marracino F, Capocci L, Giovannelli A, Madonna M, van Bergeijk J, Buttari F, van der Kam E, Maglione V . Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease . Human Molecular Genetics . 27 . 14 . 2490–2501 . Apr 2018 . 10.1093/hmg/ddy153 . 29688337 . free . 11573/1208189 . free .