Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

Abstract

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

“…Compound 31a S1P1 (Skidmore et al, 2014) SID46371153 S1P2 (Cahalan, 2014). CYM5541 S1P3 ML178 S1P4 CYM5038 (ML248) S1P4 (Urbano et al, 2011) XAX162 S1P2 (Satsu et al, 2013) CYM5520 S1P2 (Satsu et al, 2013) Table 3.…”

Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes

“…The assignment of 2s-β and 2s-β' was achieved by comparison with the literature known compound tert-butyl 6-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate and tertbutyl 5-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate. [15], [16] The signal sets of 2sα and 2s-α' did not allow for an unambiguous assignment and quantitation of these isomers. For this reason the combined amount of both minor isomers is given.…”

Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

“…Other structural elements of FTY720, such as the phenyl core and the long lipophilic tail, were also modified with other heterocyclic and aryl systems, respectively. Particularly, S1P 1 receptor agonists with oxadiazole and thiazole as heterocycle cores have been reported. − Hence, we have endeavored to develop and synthesize selective S1P 1 receptor agonists based on such a structural frame, composed of a heterocycle core with a hydrophilic west region and a lipophilic east region (Figure ). We introduced triazole or isoxazoline rings as heterocycle cores, aryl groups with various functional groups in the lipophilic east region, and mainly azetidine carboxylic acid in the hydrophilic west region.…”