Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

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 (<1 mg p.o. once daily).

Integrating the puzzle pieces: The current atomistic picture of phospholipid–G protein coupled receptor interactions

“…These data suggest that S1P 1 can also accommodate mildly bent shapes, but that S1P 2 and S1P 4 prefer more linear ligand geometries. The ability of S1P 3 to recognize both bent and linear shapes demonstrates why achieving S1P 1 -selective agonists that lack the bradycardia side effect mediated by S1P 3 action has been achieved by large jumps in structural space from the flexible phospholipid agonist analogs of S1P [11,13,17–19,21,22,25,36,41,42]. …”

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

“…17 In addition, teratogenicity has been observed in rodents, and the long half-life in humans (8 days) requires contraception for two months after stopping treatment. 18 A further challenge is identifying therapeutics with appreciable central exposure as this is believed to be necessary for success in treating MS. 19 Lastly, new agents with reduced hepatotoxicity in humans would be highly beneficial. Herein we report the discovery of APD334 (4, Figure 1), a centrally available, selective, functional antagonist of the S1P 1 receptor currently in development for the treatment of autoimmune disease.…”

<p>Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma</p>

“… 19 Studies have demonstrated that BAF312 (1 h at 1 μM) promotes significant internalization of the 91% of S1P1 receptors and downregulates S1PR1 expression. 20 In addition, a previous study found that fingolimod (FTY720), the first-generation S1PR modulator, can resensitize chemoresistant ovarian cancer cells to cisplatin by downregulating S1PR1. 21 The efficacy of BAF312 in reversing platinum-resistant ovarian cancer has not yet been evaluated in ovarian cancer.…”