The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat

PLoS ONE

Volumn 7, Issue 12, 2012, Pages

  Fryer, Ryan M ^a   Muthukumarana, Akalushi ^a   Harrison, Paul C ^a   Nodop Mazurek, Suzanne ^a   Chen, Rong Rhonda ^a   Harrington, Kyle E ^a   Dinallo, Roger M ^a   Horan, Joshua C ^a   Patnaude, Lori ^a   Modis, Louise K ^a   Reinhart, Glenn A ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKANOLAMINE; BAF 312; FINGOLIMOD; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE 1 PHOSPHATE RECEPTOR 1; SPHINGOSINE 1 PHOSPHATE RECEPTOR 3; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BRADYCARDIA; CARDIOVASCULAR EFFECT; CONTROLLED STUDY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG SELECTIVITY; DRUG SPECIFICITY; DRUG TISSUE LEVEL; HUMAN; HUMAN CELL; HYPERTENSION; IN VITRO STUDY; IN VIVO STUDY; MALE; MEAN ARTERIAL PRESSURE; NONHUMAN; RAT; REPEATED DRUG DOSE; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANIMALS; AZETIDINES; BENZYL COMPOUNDS; BRADYCARDIA; CELLS, CULTURED; DRUG EVALUATION, PRECLINICAL; HUMANS; HYPERTENSION; IMMUNOSUPPRESSIVE AGENTS; MALE; PROPYLENE GLYCOLS; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, LYSOSPHINGOLIPID; SPHINGOSINE; SUBSTRATE SPECIFICITY;

ORYCTOLAGUS CUNICULUS; RATTUS; RODENTIA;

EID: 84871701552     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0052985     Document Type: Article

References (43)

1. Sugiyama A, Aye NN, Yatomi Y, Ozaki Y, Hashimoto K, (2000) Effects of sphingosine 1-phosphate, a naturally occurring biologically active lysophospholipid, on the rat cardiovascular system. Jpn J Pharmacol 82: 338-342.
2. Sugiyama A, Yatomi Y, Ozaki Y, Hashimoto K (2000) Sphingosine 1-phosphate induces sinus tachycardia and coronary vasoconstriction in the canine heart. Cardiovasc Res 46: 119-125. S0008-6363(00)00013-4 [pii].
3. Schmouder R, Serra D, Wang Y, Kovarik JM, DiMarco J, et al. (2006) FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol 46: 895-904. 46/8/895 [pii];10.1177/0091270006289853 [doi].
4. Schubert R (2006) Sphingosine-1-phosphate in the circulatory system: Cause and therapeutic target for vascular dysfunction? Cardiovasc Res 70: 9-11. S0008-6363(06)00073-3 [pii];10.1016/j.cardiores.2006.02.012 [doi].
5. Bunemann M, Brandts B, zu Heringdorf DM, van Koppen CJ, Jakobs KH, et al. (1995) Activation of muscarinic K+ current in guinea-pig atrial myocytes by sphingosine-1-phosphate. J Physiol 489 (Pt 3): 701-707.
6. Wallstrom E, Gergely P, Nuesslein-Hildesheim B, Zecri F, Cooke N, et al. (2010) BAF312, a Selective S1P1/S1P5 Receptor Modulator, Effectively Reduces Absolute Lymphocyte Counts in Human Volunteers and Demonstrates the Relevance of S1P1 in Mediating a Transient Heart Rate Reduction. American Academy of Neurology 62nd Annual Meeting.
7. Igarashi J, Michel T (2009) Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc Res 82: 212-220. cvp064 [pii];10.1093/cvr/cvp064 [doi].
8. Means CK, Brown JH (2009) Sphingosine-1-phosphate receptor signalling in the heart. Cardiovasc Res 82: 193-200. cvp086 [pii];10.1093/cvr/cvp086 [doi].
9. Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115: 84-105. S0163-7258(07)00083-6 [pii];10.1016/j.pharmthera.2007.04.006 [doi].
10. Shimizu H, Takahashi M, Kaneko T, Murakami T, Hakamata Y, et al. (2005) KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts. Circulation 111: 222-229. 01.CIR.0000152101.41037.AB [pii];10.1161/01.CIR.0000152101.41037.AB [doi].
11. Hale JJ, Doherty G, Toth L, Mills SG, Hajdu R, et al. (2004) Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists. Bioorg Med Chem Lett 14: 3501-3505. 10.1016/j.bmcl.2004.04.070 [doi];S0960894X04005803 [pii].
12. Demont EH, Arpino S, Bit RA, Campbell CA, Deeks N, et al. (2011) Discovery of a brain-penetrant S1P-sparing direct agonist of the S1P and S1P receptors efficacious at low oral dose. J Med Chem 54: 6724-6733. 10.1021/jm200609t [doi].
13. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, et al. (2012) The selective S1P receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate: translation from preclinical to clinical studies. Br J Pharmacol. 10.1111/j.1476-5381.2012.02061.x [doi].
14. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, et al. (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362: 402-415. NEJMoa0907839 [pii];10.1056/NEJMoa0907839 [doi].
15. Guo J, MacDonell KL, Giles WR, (1999) Effects of sphingosine 1-phosphate on pacemaker activity in rabbit sino-atrial node cells. Pflugers Arch 438: 642-648.
16. Himmel HM, Meyer Zu HD, Graf E, Dobrev D, Kortner A, et al. (2000) Evidence for Edg-3 receptor-mediated activation of I(K.ACh) by sphingosine-1-phosphate in human atrial cardiomyocytes. Mol Pharmacol 58: 449-454.
17. Means CK, Miyamoto S, Chun J, Brown JH (2008) S1P1 receptor localization confers selectivity for Gi-mediated cAMP and contractile responses. J Biol Chem 283: 11954-11963. M707422200 [pii];10.1074/jbc.M707422200 [doi].
18. Igarashi J, Michel T (2008) S1P and eNOS regulation. Biochim Biophys Acta 1781: 489-495. S1388-1981(08)00124-8 [pii];10.1016/j.bbalip.2008.06.008 [doi].
19. Tawadrous MN, Mabuchi A, Zimmermann A, Wheatley AM (2002) Effects of immunosuppressant FTY720 on renal and hepatic hemodynamics in the rat. Transplantation 74: 602-610. 10.1097/01.TP.0000021368.09132.D6 [doi].
20. Pan, S, Gao, W, Gray, N, Mi, Y, and Fan, Y, inventors; 12-2-2004) Immunosuppressant Compounds and Compositions. United States patent application WO 2004/103306 A2.
21. Liu, Y, Papoutsakis, D, and Roddy, E, inventors; 6-24-2010) New Polymorphic form of 1-(4-{L-(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxy-imino]-ethyl)-2-ethyl-benzyl L)-azetidine-3-carboxylic. United States patent application WO 2010/071794 A1.
22. Durand P, Peralba PSF, Renaut P, (2000) A new efficient synthesis of hte immunosuppressive agent FTY-720. Synthesis 2000: 505-506.
23. Kym PR, Souers AJ, Campbell TJ, Lynch JK, Judd AS, et al. (2006) Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists. J Med Chem 49: 2339-2352. 10.1021/jm0512286 [doi].
24. Segreti JA, Marsh KC, Polakowski JS, Fryer RM (2008) Evoked changes in cardiovascular function in rats by infusion of levosimendan, OR-1896 [(R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamid e], OR-1855 [(R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], dobutamine, and milrinone: comparative effects on peripheral resistance, cardiac output, dP/dt, pulse rate, and blood pressure. J Pharmacol Exp Ther 325: 331-340. jpet.107.132530 [pii];10.1124/jpet.107.132530 [doi].
25. Banfor PN, Franklin PA, Segreti JA, Widomski DL, Davidsen SK, et al. (2009) ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats. J Cardiovasc Pharmacol 53: 173-178. 10.1097/FJC.0b013e3181993493 [doi].
26. Franklin PH, Banfor PN, Tapang P, Segreti JA, Widomski DL, et al. (2009) Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther 329: 928-937. jpet.108.144816 [pii];10.1124/jpet.108.144816 [doi].
27. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277: 21453-21457. 10.1074/jbc.C200176200 [doi];C200176200 [pii].
28. Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, et al. (2009) Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 5: 428-434. nchembio.173 [pii];10.1038/nchembio.173 [doi].
29. Jongsma M, van UJ, van Loenen PB, Michel MC, Peters SL, et al. (2009) Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P(3)). Br J Pharmacol 156: 1305-1311. BPH134 [pii];10.1111/j.1476-5381.2009.00134.x [doi].
30. Ochi R, Momose Y, Oyama K, Giles WR (2006) Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents. Cardiovasc Res 70: 88-96. S0008-6363(06)00027-7 [pii];10.1016/j.cardiores.2006.01.010 [doi].
31. Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, et al. (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9: 883-897. nrd3248 [pii];10.1038/nrd3248 [doi].
32. Lewis N, Haxhinasto S, Anderson S, Stefanopoulos D, Fogal S, et al. (2012) Monocyte trafficking is restricted by sphingosine-1-phosphate receptor modulators independently of S1P3. Journal of Immunology In Revision.
33. Tao R, Hoover HE, Zhang J, Honbo N, Alano CC, et al. (2009) Cardiomyocyte S1P1 receptor-mediated extracellular signal-related kinase signaling and desensitization. J Cardiovasc Pharmacol 53: 486-494. 10.1097/FJC.0b013e3181a7b58a [doi].
34. Jo E, Sanna MG, Gonzalez-Cabrera PJ, Thangada S, Tigyi G, et al. (2005) S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate. Chem Biol 12: 703-715. S1074-5521(05)00133-X [pii];10.1016/j.chembiol.2005.04.019 [doi].
35. O'Connor P, Comi G, Montalban X, Antel J, Radue EW, et al. (2009) Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 72: 73-79. 72/1/73 [pii];10.1212/01.wnl.0000338569.32367.3d [doi].
36. Gergely P, Wallstrom E, Nuesslein-Hildesheim B, Bruns C, Zecri F,et al. (200) Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans. 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis.
37. Fryer RM, Harrison PC, Muthukumarana A, Nodop Mazurek SG, Ng KJ, et al. (2012) Strategic integration of in vivo cardiovascular models during lead optimization: predictive value of 4 models independent of species, route of administration, and influence of anesthesia. J Cardiovasc Pharmacol 59: 369-376. 10.1097/FJC.0b013e31824485dd [doi].
38. Saha A, Yu X, Lin J, Lobera M, Sharadendu A, et al. (2011) Benzofuran derivatives as potent, orally active S1P1 receptor agonists: a preclinical lead molecule in MS. ACS Medicinal Chemistry Letters 2: 97-101.
39. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, et al. (2008) Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 154: 1465-1473. bjp2008229 [pii];10.1038/bjp.2008.229 [doi].
40. Fujishiro J, Kudou S, Iwai S, Takahashi M, Hakamata Y, et al. (2006) Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation. Transplantation 82: 804-812. 10.1097/01.tp.0000232687.78242.cd [doi];00007890-200609270-00014 [pii].
41. Murakami A, Takasugi H, Ohnuma S, Koide Y, Sakurai A, et al. (2010) Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist. Mol Pharmacol 77: 704-713. mol.109.061481 [pii];10.1124/mol.109.061481 [doi].
42. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, et al. (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther 309: 758-768. 10.1124/jpet.103.062828 [doi];jpet.103.062828 [pii].
43. Ota H, Beutz MA, Ito M, Abe K, Oka M, et al. (2011) S1P(4) receptor mediates S1P-induced vasoconstriction in normotensive and hypertensive rat lungs. Pulm Circ 1: 399-404. 10.4103/2045-8932.87309 [doi];PC-1-399 [pii].