Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy

Abstract

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives

“…With an optimally substituted biphenyl lipophilic group, the truncation of the polar headgroup to a benzoic acid ( 36 ) provided a compound with potent binding to S1P 1 ( K i 2.9 nM) and only weak affinity for S1P 3 . On the same template, extension of the acidic group further from the phenyl ring led to a 3-fold increase in S1P 1 binding activity while maintaining selectivity against S1P 3 in 37 .…”

“…In a similar situation is naphthalene 79 , from Novartis, for which a synthetic effort was described whose goal was the delivery of multikilogram quantities . Finally, Merck Serono described an in vitro and in vivo selection process leading to the identification of 78 as a clinical candidate . Notable in 78 is the disposition of the lipophilic and zwitterionic groups across the phenyl ring, which utilizes the less common meta rather than para orientation, a feature that brought in desired activity against S1P 5 and improved efficacy in a mouse model for multiple sclerosis.…”

Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer

“…31,32 Our screening focused on S1P 1 selective ligands because the efficacy of 2 in MS is attributed to its high binding potency toward to S1P 1 . 6,35 As shown in Table 2, 28c has a high potency (IC 50 = 2.63 ± 0.27 nM) and selectivity for S1P 1 over S1P 2 or S1P 3 (IC 50 > 1000 nM).…”

“…30 Here, we present the synthesis and screening of fluorine-containing ligands based on reported compounds with either a benzoxazole core 31 or an oxadiazole core. 32,33 Compound 28c was identified as a potent and selective ligand for S1P 1 over S1P 2 or S1P 3 in our competitive binding assay, 34 so was 18 F-labeled for biological evaluation in the mouse model of LPS-induced liver injury.…”

“…We have also used the wealth of knowledge in this field to investigate PET radiotracers for S1P receptors using rodent models of human disease. − Our group previously reported the radiosynthesis of the 11 C-labeled S1P 1 selective ligand 3-((2-fluoro-4-(5-(2′-methyl-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)­benzyl)-(methyl)­amino)-propanoic acid 5 ([ 11 C]­TZ3321, Figure ) and demonstrated the feasibility of PET imaging S1P 1 as a measure of inflammatory response in both the femoral artery wire-injury mouse model of restenosis and in the experimental autoimmune encephalomyelitis (EAE) rat model of multiple sclerosis (MS) . Here, we present the synthesis and screening of fluorine-containing ligands based on reported compounds with either a benzoxazole core or an oxadiazole core. , Compound 28c was identified as a potent and selective ligand for S1P 1 over S1P 2 or S1P 3 in our competitive binding assay, so was 18 F-labeled for biological evaluation in the mouse model of LPS-induced liver injury.…”