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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900263

Citations 4

Authors

Lewis D Pennington

Kelvin K C Sham

Alexander J Pickrell

Paul E Harrington

Michael J Frohn

Brian A Lanman

Anthony B Reed

Michael D Croghan

Matthew R Lee

Han Xu

Michele McElvain

Yang Xu

Xuxia Zhang

Michael Fiorino

Michelle Horner

Henry G Morrison

Heather A Arnett

Christopher Fotsch

Min Wong

Victor J Cee

Affiliations

Soon will be listed here.

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.

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References

Fujiwara Y, Osborne D, Walker M, Wang D, Bautista D, Liliom K . Identification of the hydrophobic ligand binding pocket of the S1P1 receptor. J Biol Chem. 2006; 282(4):2374-85. PMC: 3446783. DOI: 10.1074/jbc.M609648200. View

Marsolais D, Rosen H . Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov. 2009; 8(4):297-307. PMC: 4455967. DOI: 10.1038/nrd2356. View

Albert R, Hinterding K, Brinkmann V, Guerini D, Muller-Hartwieg C, Knecht H . Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J Med Chem. 2005; 48(16):5373-7. DOI: 10.1021/jm050242f. View

Kharel Y, Lee S, Snyder A, Sheasley-ONeill S, Morris M, Setiady Y . Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem. 2005; 280(44):36865-72. DOI: 10.1074/jbc.M506293200. View

Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D . A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol. 2006; 13(11):1227-34. DOI: 10.1016/j.chembiol.2006.09.017. View

Kihara A, Mitsutake S, Mizutani Y, Igarashi Y . Metabolism and biological functions of two phosphorylated sphingolipids, sphingosine 1-phosphate and ceramide 1-phosphate. Prog Lipid Res. 2007; 46(2):126-44. DOI: 10.1016/j.plipres.2007.03.001. View

Rivera J, Proia R, Olivera A . The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008; 8(10):753-63. PMC: 2600775. DOI: 10.1038/nri2400. View

Schmouder R, Serra D, Wang Y, Kovarik J, DiMarco J, Hunt T . FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol. 2006; 46(8):895-904. DOI: 10.1177/0091270006289853. View

Brinkmann V, Davis M, Heise C, Albert R, Cottens S, Hof R . The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002; 277(24):21453-7. DOI: 10.1074/jbc.C200176200. View

10.

Cyster J . Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005; 23:127-59. DOI: 10.1146/annurev.immunol.23.021704.115628. View

11.

Ross W . The preparation of some 4-substituted nicotinic acids and nicotinamides. J Chem Soc Perkin 1. 1966; 20:1816-21. DOI: 10.1039/j39660001816. View

12.

Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J . Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002; 296(5566):346-9. DOI: 10.1126/science.1070238. View

13.

Gonzalez-Cabrera P, Jo E, Sanna M, Brown S, Leaf N, Marsolais D . Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. Mol Pharmacol. 2008; 74(5):1308-18. PMC: 2575047. DOI: 10.1124/mol.108.049783. View

14.

Sanna M, Liao J, Jo E, Alfonso C, Ahn M, Peterson M . Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004; 279(14):13839-48. DOI: 10.1074/jbc.M311743200. View

15.

Brinkmann V . FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009; 158(5):1173-82. PMC: 2782328. DOI: 10.1111/j.1476-5381.2009.00451.x. View

16.

Cee V, Frohn M, Lanman B, Golden J, Muller K, Neira S . Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5. ACS Med Chem Lett. 2014; 2(2):107-12. PMC: 4018127. DOI: 10.1021/ml100306h. View

17.

Jo E, Sanna M, Gonzalez-Cabrera P, Thangada S, Tigyi G, Osborne D . S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate. Chem Biol. 2005; 12(6):703-15. DOI: 10.1016/j.chembiol.2005.04.019. View

18.

Hale J, Lynch C, Neway W, Mills S, Hajdu R, Keohane C . A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists. J Med Chem. 2004; 47(27):6662-5. DOI: 10.1021/jm0492507. View

19.

WILEY P . The reaction of amides with isocyanates. J Am Chem Soc. 1949; 71(4):1310. DOI: 10.1021/ja01172a047. View

20.

Takabe K, Paugh S, Milstien S, Spiegel S . "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008; 60(2):181-95. PMC: 2695666. DOI: 10.1124/pr.107.07113. View