4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P₁

Abstract

The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = −78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2–5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.

An update on sphingosine-1-phosphate receptor 1 modulators

“…89,90 The compound is characterized by its remarkable lack of a polar head group. Thus, it does not require bioactivation by phosphorylation, and yet is highly specific for S1P 1 , with a >100–fold selectivity relative to S1P 2–5 .…”

“…Thus, it does not require bioactivation by phosphorylation, and yet is highly specific for S1P 1 , with a >100–fold selectivity relative to S1P 2–5 . 65,89,91 The carbamoylnicotinamide synthesized by Pennington et al causes substantial depletion of lymphocyte circulation (78–81% depletion in rats) 24 hrs after a single oral dose of 1 mg/kg, and has an EC 50 value of 35 nM with 96% efficacy. 89 Respective quinolinone derivatives were reported to inhibit lymphocyte recirculation and egress with equivalent S1P 1 selectivity.…”

“…Pennington and Harrington et al described a series of novel S1P 1 agonists based on the S1P receptor selective carbamoylnicotinamide in 2011 and 2012. 89,90 The compound is characterized by its remarkable lack of a polar head group. Thus, it does not require bioactivation by phosphorylation, and yet is highly specific for S1P 1 , with a >100–fold selectivity relative to S1P 2–5 .…”

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

“…The trends in all these studies suggest that anionic headgroups with charges delocalized over three atoms are better able to activate all S1P receptors than anionic headgroups with reduced overall charge, or charge shared only by two atoms as in the carboxylate headgroup. Highly delocalized negative charge is not an absolute requirement, however, as highly potent non-lipid molecules with carboxylate headgroups [11–18] as well as uncharged trifluoromethyl [19,20] and other headgroups [21–25] combined with a variety of aromatic and heteroaromatic linker/tail combinations have been reported. The headgroup pocket also seems to be limited in size, as the sulfur atom in the thiophosphate is substantially larger than the corresponding oxygen atomin a phosphate group.…”

“…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]. …”