1. Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose
- Author
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Karen Louise Philpott, Robert J. Watson, Jason Witherington, Greg J. Osborne, Terry Panchal, Simon Taylor, Nigel Deeks, Tom D. Heightman, James Gray, Umesh Kumar, Simon J. Dowell, Pam Gaskin, Lee Andrew Harrison, Robert Willis, Colin A. Campbell, Sandra Arpino, Sapna Desai, Rino A. Bit, Mary A. Morse, Emmanuel Hubert Demont, Andrea C. Haynes, Philip G. Humphreys, and Duncan S. Holmes
- Subjects
Agonist ,medicine.drug_class ,Chemistry ,organic chemicals ,Multiple sclerosis ,Central nervous system ,Pharmacology ,medicine.disease ,Fingolimod ,Therapeutic index ,medicine.anatomical_structure ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Potency ,lipids (amino acids, peptides, and proteins) ,Receptor ,medicine.drug - Abstract
2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (
- Published
- 2011