Discovery of a Selective S1P₁ Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

Abstract

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3−5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists

“…The CCR4 cell line was obtained from DiscoveRx and grown in the manufacturer׳s suggested medium. Agonist induced coupling was detected as described ( Demont et al, 2011 ).…”

Implication of sphingosin-1-phosphate in cardiovascular regulation

“…Although S1P3, not S1P1, mediates a bradycardic effect in rodent (24, 26, 34), selective activation of S1P1 can also induces a rapid and transient bradycardia in humans (35). S1P1 agonist-induced bradycardic response in human myocytes can be explained by the activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels (35).…”

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]. …”