Medicinal Chemistry International

DRUG PATENTS INTERNATIONAL

gsk 2262167

CAS, 1165924-28-6 FREE FORM

1165923-54-5 NA SALT

1458576-13-0 MONOHYDRATE

C₂₅ H₂₆ N₄ O₄

3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate

2(1H)- Isoquinolinepropanoic acid, 6-[5-[3-cyano-4-(1-methylethoxy)phenyl]-1,2,4-oxadiazol-3- yl]-3,4-dihydro-5-methyl-

3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid

Sphingosine 1 -phosphate (S1 P) is a bioactive lipid mediator formed by the phosphorylation of sphingosine by sphingosine kinases and is found in high levels in the blood. It is produced and secreted by a number of cell types, including those of hematopoietic origin such as platelets and mast cells (Okamoto et al 1998 J Biol Chem 273(42):27104; Sanchez and HIa 2004, J Cell Biochem 92:913). It has a wide range of biological actions, including regulation of cell proliferation, differentiation, motility, vascularisation, and activation of inflammatory cells and platelets (Pyne and Pyne 2000, Biochem J. 349: 385). Five subtypes of S1 P responsive receptor have been described, S1 P1 (Edg-1 ), S1 P2 (Edg-5), S1 P3 (Edg-3), S1 P4 (Edg-6), and S1 P5 (Edg-8), forming part of the G-protein coupled endothelial differentiation gene family of receptors (Chun et al 2002 Pharmacological Reviews 54:265, Sanchez and HIa 2004 J Cellular Biochemistry, 92:913). These 5 receptors show differential mRNA expression, with S1 P1-3 being widely expressed, S1 P4 expressed on lymphoid and hematopoietic tissues and S1 P5 primarily in brain and to a lower degree in spleen. They signal via different subsets of G proteins to promote a variety of biological responses (Kluk and HIa 2002 Biochem et Biophysica Acta 1582:72, Sanchez and HIa 2004, J Cellular Biochem 92:913).

Proposed roles for the S1 P1 receptor include lymphocyte trafficking, cytokine induction/suppression and effects on endothelial cells (Rosen and Goetzl 2005 Nat Rev Immunol. 5:560). Agonists of the S1 P1 receptor have been used in a number of autoimmune and transplantation animal models, including Experimental Autoimmune Encephalomelitis (EAE) models of MS, to reduce the severity of the induced disease (Brinkman et al 2003 JBC 277:21453; Fujino et al 2003 J Pharmacol Exp Ther 305:70; Webb et al 2004 J Neuroimmunol 153:108; Rausch et al 2004 J Magn Reson Imaging 20:16). This activity is reported to be mediated by the effect of S1 P1 agonists on lymphocyte circulation through the lymph system. Treatment with S1 P1 agonists results in the sequestration of lymphocytes within secondary lymphoid organs such as the lymph nodes, inducing a reversible peripheral lymphopoenia in animal models (Chiba et al 1998, J Immunology 160:5037, Forrest et al 2004 J Pharmacol Exp Ther 309:758; Sanna et al 2004 JBC 279:13839). Published data on agonists suggests that compound treatment induces loss of the S1 P1 receptor from the cell surface via internalisation (Graler and Goetzl 2004 FASEB J 18:551 ; Matloubian et al 2004 Nature 427:355; Jo et al 2005 Chem Biol 12:703) and it is this reduction of S1 P1 receptor on immune cells which contributes to the reduction of movement of T cells from the lymph nodes back into the blood stream.

S1 P1 gene deletion causes embryonic lethality. Experiments to examine the role of the S1 P1 receptor in lymphocyte migration and trafficking have included the adoptive transfer of labelled S1 P1 deficient T cells into irradiated wild type mice. These cells showed a reduced egress from secondary lymphoid organs (Matloubian et al 2004 Nature 427:355).

S1 P1 has also been ascribed a role in endothelial cell junction modulation (Allende et al 2003 102:3665, Blood Singelton et al 2005 FASEB J 19:1646). With respect to this endothelial action, S1 P1 agonists have been reported to have an effect on isolated lymph nodes which may be contributing to a role in modulating immune disorders. S1 P1 agonists caused a closing of the endothelial stromal 'gates' of lymphatic sinuses which drain the lymph nodes and prevent lymphocyte egress (Wei wt al 2005, Nat. Immunology 6:1228).

The immunosuppressive compound FTY720 (JP1 1080026-A) has been shown to reduce circulating lymphocytes in animals and man, have disease modulating activity in animal models of immune disorders and reduce remission rates in relapsing remitting Multiple Sclerosis (Brinkman et al 2002 JBC 277:21453, Mandala et al 2002 Science 296:346, Fujino et al 2003 J Pharmacology and Experimental Therapeutics 305:45658, Brinkman et al 2004 American J Transplantation 4:1019, Webb et al

2004 J Neuroimmunology 153:108, Morris et al 2005 EurJ Immunol 35:3570, Chiba

2005 Pharmacology and Therapeutics 108:308, Kahan et al 2003, Transplantation 76:1079, Kappos et al 2006 New Eng J Medicine 335:1124). This compound is a prodrug that is phosphorylated in vivo by sphingosine kinases to give a molecule that has agonist activity at the S1 P1 , S1 P3, S1 P4 and S1 P5 receptors. Clinical studies have demonstrated that treatment with FTY720 results in bradycardia in the first 24 hours of treatment (Kappos et al 2006 New Eng J Medicine 335:1124). The bradycardia is thought to be due to agonism at the S1 P3 receptor, based on a number of cell based and animal experiments. These include the use of S1 P3 knock- out animals which, unlike wild type mice, do not demonstrate bradycardia following FTY720 administration and the use of S1 P1 selective compounds (Hale et al 2004 Bioorganic & Medicinal Chemistry Letters 14:3501 , Sanna et al 2004 JBC 279:13839, Koyrakh et al 2005 American J Transplantation 5:529).

Hence, there is a need for S1 P1 receptor agonist compounds with selectivity over S1 P3 which might be expected to show a reduced tendency to induce bradycardia.

The following patent applications describe oxadiazole derivatives as S1 P1 agonists: WO03/105771 , WO05/058848, WO06/047195, WO06/100633, WO06/115188, WO06/131336, WO07/024922 and WO07/1 16866.

The following patent applications describe tetrahydroisoquinolinyl-oxadiazole derivatives as S1 P receptor agonists: WO06/064757, WO06/001463, WO04/1 13330.

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paper

Organic Process Research & Development (2013), 17(10), 1239-1246.

Robert M. Harris *, Benjamin I. Andrews , Stacy Clark , Jason W. B. Cooke , John C. S. Gray , andStephanie Q. Q. Ng

Chemical Development, GlaxoSmithKline Research and Development Ltd., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Org. Process Res. Dev., 2013, 17 (10), pp 1239–1246

DOI: 10.1021/op400162p

A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P₁ receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.

http://pubs.acs.org/doi/abs/10.1021/op400162p?tokenDomain=campaign&tokenAccess=noteworthy&forwardService=showFullText&journalCode=oprdfk

AND

http://pubs.acs.org/doi/suppl/10.1021/op400162p/suppl_file/op400162p_si_001.pdf

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Will watson

http://www.allfordrugs.com/scientific-update/

WILL WATSON in ACS noteworthy chemistry wrote

http://www.acs.org/content/acs/en/noteworthy-chemistry/2014-archive/june-23.html

Researchers make a profit from a pilot plant reaction. R. H. Harris and co-workers at GlaxoSmithKline Research and Development (Stevenage, UK) developed a “fit-for-purpose” method for scaling up the synthesis of a sphingosine 1-phosphate receptor agonist. They shortened the route to the 5-hydroxytetrahydroisoquinoline intermediate from eight to two steps by carrying out a Robinson annulation on N-Boc-4-piperidone followed by aromatization of the cyclohexane ring. (Boc is tert-butoxycarbonyl.)

The authors found, however, that only a Saegusa oxidation that uses stoichiometric quantities of Pd(OAc)₂ catalyst gives good conversion in the aromatization. Optimizing the workup by adding HCO₂K at the end of the reaction to reduce the Pd(II) and precipitate the palladium as Pd(0) made it possible to recover 10.3 kg of the 10.5kg of palladium used in the pilot plant.

The price of palladium doubled during the campaign, so GlaxoSmithKline sold the palladium back to supplier Johnson Matthey at a profit of UK£62,500. Subsequently, the authors developed a more economical CuBr₂-mediated aromatization reaction. (Org. Process Res. Dev. 2013, 17, 1239–1246; Will Watson)

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ACS Medicinal Chemistry Letters (2011), 2(6), 444-449.

paper

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P₁ and S1P₃₋₅). It has been postulated that fingolimod's efficacy is due to S1P₁ agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P₃ agonism. We have discovered a series of selective S1P₁ agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P₃-sparing, orally active S1P₁ agonist. Compound20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P₃ is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

http://pubs.acs.org/doi/abs/10.1021/ml2000214

Discovery of a Selective S1P₁ Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

^†Immuno Inflammation Center of Excellence for Drug Discovery and ^‡Platform Technology and Science,GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom

ACS Med. Chem. Lett., 2011, 2 (6), pp 444–449

DOI: 10.1021/ml2000214

--

Journal of Medicinal Chemistry (2011), 54(19), 6724-6733

http://pubs.acs.org/doi/abs/10.1021/jm200609t

Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

^†Immuno Inflammation Center of Excellence for Drug Discovery, ^‡Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom

Neurology Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom

J. Med. Chem., 2011, 54 (19), pp 6724–6733

DOI: 10.1021/jm200609t

Publication Date (Web): August 15, 2011

Telephone: + 44 1438 764319. Fax: + 44 1438 768302. E-mail: emmanuel.h.demont@gsk.com.

Abstract

Introduction

2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (Fingolimod, FTY720, Figure 1)(1) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Administration of 1 leads to the sequestration of lymphocytes in secondary lymphoid organs and consequently to a reduction of lymphocyte count in the peripheral blood. 1 is phosphorylated in vivo by sphingosine kinase-2(2, 3) to form FTY720-P 2, a potent agonist of four of the five G-protein-coupled receptors (S1P₁, S1P_3–5) associated with the lysolipid sphingosine 1-phosphate (S1P) 3. Agonism of the S1P₁ receptor by S1P is required to induce egress of T cells from lymphoid organs and 2 acts as a functional antagonist by internalizing the receptor.(4, 5) The cardiovascular side effects observed in treated patients (bradycardia and hypertension) have been linked to partial agonism of the S1P₃ receptor,(6, 7) although more recent findings from human studies indicate that S1P₁ may mediate the transient effects on heart rate.(8) Owing to its lipophilic nature, 1 is able to cross the blood-brain barrier (BBB)(9) where 2 interacts with S1P receptors present on astrocytes (S1P₁) and on oligodendrocytes (S1P₅). Recent publications suggest this may play a role in fingolimod’s efficacy in the treatment of patients with RRMS.(10, 11)

Excellent (>1000 fold) selectivity over S1P₃ can be achieved with agonists such as AMG 369(15)6 or PF-991(16)7, but these molecules, as our own S1P₃-sparing agonist 8(17) (Table 1), are zwitterions and are therefore likely to have poor CNS penetration. (18) Typically, in our hands, 8 proved to be a P-gp substrate (with an efflux ratio in a human MDR1 transfected MDCK type 2 cell line of 0.5 and 6.0 in the presence and absence of a P-gp inhibitor, respectively). Interestingly, 8 shows no activity at S1P₂ and S1P₄, and is a partial agonist of the S1P₅ receptor with similar potency to that at S1P₁.(19)

Table 1. Activity of 2 and 8 at S1P_1-5 Receptors

	pEC₅₀ (maximum activation %)
human receptor (assay)^a	2^b	8
S1P₁ (β-arrestin)	7.7 (99), n = 44	8.25 (94), n = 13
S1P₂ (yeast)	<4.5, n = 5	<4.48 (01), n = 6
S1P₃ (GTPγS)	8.3 (62), n = 38	<4.5 (35), n = 6
S1P₄ (aequorin)	6.7 (48), n = 2	<4.38 (03), n = 4
S1P₅ (aequorin)	7.2 (62), n = 2	6.79 (77), n = 6

a

See the Supporting Information for details.

b

For comparative published values, see ref 35.

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WO 2009080724

http://www.google.com/patents/WO2009080724A1?cl=en

Example 11

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt

Trifluoroacetic acid (3ml) was added to an ice cooled solution of 1 ,1-dimethylethyl 6- (5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro- 2(1 H)-isoquinolinecarboxylate (Preparation 22; 486mg, 1.02mmol) in dichloromethane (3ml). The reaction mixture was stirred at O⁰C for 30 minutes. The solvent was evaporated and the residue co-evaporated from toluene (x2). Trituration of the residue with diethyl ether gave the title compound as a colourless solid which was filtered off and dried (485mg). ¹H NMR (400 MHz, CDCI₃) δ: 1.48 (6H, d), 2.54 (3H, s), 3.09 (2H, m), 3.5 (2H, obscured by residual solvent), 4.36 (2H, s), 4.80 (1 H, m), 7.08-7.15 (2H, m), 7.85 (1 H, d), 8.33 (1 H, d), 8.42 (1 H, s), 10.20 (2H, br s). MS m/z 375 [MH]⁺.

Example 13 3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid sodium salt

2M sodium hydroxide (2ml) was added to a solution of ethyl 3-[6-(5-{3-cyano-4-[(1- methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)- isoquinolinyl]propanoate (Preparation 24; 80mg, 0.17mmol) in ethanol (2ml) at 6O⁰C. The reaction mixture was stirred at 6O⁰C for 2 hours, cooled to room temperature and diluted with water (2ml). The solid was filtered off, washed with a small amount of water and dried to give the title compound as a colourless solid (55mg). ¹H NMR (400 MHz, deDMSO) δ: 1.39 (6H, d), 2.08 (2H, t), 2.44 (3H, s), 2.59-2.78 (6H, m), 3.56 (2H, s), 4.98 (1 H, m), 7.09 (1 H, d), 7.55 (1 H, d), 7.65 (1 H, d), 8.40 (1 H, dd), 8.50 (1 H, s). MS m/z 447 [MH]⁺.

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SEE

CN 103251950

http://www.google.com/patents/CN103251950A?cl=en

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WO 2010146105

http://www.google.com/patents/WO2010146105A1?cl=en

Preparation 12

6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride

CIH

To a solution of 1 ,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4- oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (1.85g, 3.8 mmol, WO 2009080724) in 1 ,4-dioxane (10ml) at room temperature under nitrogen was added slowly hydrogen chloride in 1 ,4-dioxane (4N, 30ml, 120 mmol) and the resulting mixture was stirred at room temperature for 3.5h. Removal of the solvent and co-evaporation of the residue with diethyl ether gave 6-(5-{3-chloro-4-[(1- methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (1.65g, 103%) as a white solid. LCMS (Method HpH): Retention time 1.43min, MH⁺ = 384

Preparation 25

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile hydrochloride

To a solution of 1 ,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4- oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (3.4g, 7.2 mmol) in 1 ,4-dioxane (20ml) at room temperature under nitrogen was added a hydrogen chloride in 1 ,4-dioxane (4M, 17.9ml, 72 mmol) and the resulting mixture was stirred at this temperature for 5.5h, stored in a freezer overnight and then concentrated. The residue was co-evaporated with diethyl ether to give 2-[(1- methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5- yl]benzonitrile hydrochloride (2.88g, 98%) as a white solid. LCMS (Method HpH): Retention time 1.21 min, MH⁺ = 375

Preparation 25: alternative procedure

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile trifluoroacetate

Trifluoroacetic acid (15ml) was added to an ice cooled solution of 1 ,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4- dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (2.9g, 6.1 mmol) in DCM (20ml). The reaction mixture was stirred at 0⁰C for 1 h and the solvent evaporated. The residue was co-evaporated with toluene (x2) and triturated with diethyl ether. The solid was isolated by filtration and washed with diethyl ether to give 2-[(1- methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5- yl]benzonitrile trifluoroacetate (2.7g, 90%) as a colourless solid. LCMS (Method formate): Retention time 0.90min, MH⁺ = 375

1 H NMR (D₆-DMSO): δH 9.16(2H, bs), 8.51 ,(1 H, d), 8.40(1 H, dd), 7.78(1 H, d), 7.57(1 H, d), 7.29(1 H, d), 4.98(1 H, m), 4.38(2H, s), 3.49(2H, partially obscured by water), 2.99(2H, t), 2.47(3H, s), 1.39(6H, d).

Preparation 25: alternative procedure

2-[(1 -methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile hydrochloride

1 ,1-Dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)- 5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (50.Og, 1 10 mmol) in DCM (150ml) was added drop-wise to hydrogen chloride in 1 ,4-dioxane (4M, 263ml, 1 100 mmol) and the mixture was stirred for 2h at room temperature, giving a pale yellow suspension. The mixture was diluted with diethyl ether (500ml), stirred for 20min. Then solid was isolated by filtration, washed with diethyl ether (3x 100ml) and dried in vacuo at 55°C overnight to give 2-[(1-methylethyl)oxy]-5-[3-(5- methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (39.8g, 92%) as white solid.

LCMS (Method HpH): Retention time 1.22min, MH⁺ = 375

1 H NMR (D₆-DMSO) includes: δH 9.49(2H, bs), 8.51 (1 H, d), 8.40(1 H, dd), 7.77(1 H, d), 7.56(1 H, d), 7.29(1 H, d), 4.98(1 H, m), 4.35(2H, m), 3.44-3.36(2H, largely obscured by water), 3.00(2H, t), 2.47(3H, s), 1.39(6H, d).

Preparation 27

3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid sodium salt

Sodium hydroxide (2M, 1 ml) was added to a stirred solution of ethyl 3-[6-(5-{3-cyano- 4-[(1-methylethyl)oxy]phenyl}-1 _!2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)- isoquinolinyl]propanoate (Preparation 26) (200mg, 0.42 mmol) in ethanol (1 ml). The reaction mixture was stirred at 50⁰C for 1 h then cooled and the ethanol evaporated. The residue was diluted with water (2ml) and stirred for 15min. The precipitate was isolated by filtration, washed with water and dried under vacuum to give 3-[6-(5-{3- cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro- 2(1 H)-isoquinolinyl]propanoic acid sodium salt (150mg, 76%) as a colourless solid. LCMS (Method formate): Retention time 0.92min, MH⁺ = 447

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SEE

Xenobiotica (2012), 42(7), 671-686

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Martini, S.; Peters, H.; Böhler, T.; Budde, K.Current Perspectives on FTY720 Expert Opin. Invest. Drugs 2007, 16, 505– 518
2.
Billich, A.; Bornancin, F.; Dévay, P.; Mechtcheriakova, D.; Urtz, N.; Baumruker, T.Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases J. Biol. Chem. 2003, 278, 47408– 47415
3.
Albert, R.; Hinterding, K.; Brinkmann, V.; Guerini, D.; Müller-Hartwieg, C.; Knecht, H.; Simeon, C.; Streiff, M.; Wagner, T.; Welzenbach, K.; Zécri, F.; Zollinger, M.; Cooke, N.; Francotte, E.Novel Immunomodulator FTY720 Is Phosphorylated in Rats and Humans to Form a Single Stereoisomer. Identification, Chemical Proof, and Biological Characterisation of the Biologically Active Species and Its Enantiomer J. Med. Chem. 2005, 48, 5373– 5377
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Matloubian, M.; Lo, C. G.; Cinamon, G.; Lesneski, M. J.; Xu, Y.; Brinkmann, V.; Allende, M. L.; Proia, R. L.; Cyster, J. G.Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 Nature 2004, 427, 355– 360
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Wei, S. H.; Rosen, H.; Matheu, M. P.; Sanna, M. G.; Wang, S.-K.; Jo, E.; Wong, C.-H.; Parker, I.; Cahalan, M. D.Sphingosine 1-Phosphate Type 1 receptor Agonism Inhibits Transendothelial Migration of Medullary T Cells to Lymphatic Sinuses Nat. Immunol. 2005, 6, 1228– 1235
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Forrest, M.; Sun, S.-Y.; Hajdu, R.; Bergstrom, J.; Card, D.; Doherty, G.; Hale, J.; Keohane, C.; Meyers, C.; Milligan, J.; Mills, S.; Nomura, N.; Rosen, H.; Rosenbach, M.; Shei, G.-J.; Singer, I. I.; Tian, M.; West, S.; White, V.; Xie, J.; Proia, R. L.; Mandala, S.Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes J. Pharmacol. Exp. Ther. 2004, 309, 758– 768
7.
Sanna, M. G.; Liao, J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.; Peterson, M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Gray, N.; Rosen, H.Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P₁ and S1P₃, Respectively, Regulate Lymphocyte Recirculation and Heart Rate J. Biol. Chem. 2004, 279, 13839– 13848
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Gergely, P.; Wallström, E.; Nuesslein-Hildesheim, B.; Bruns, C.; Zécri, F.; Cooke, N.; Traebert, M.; Tuntland, T.; Rosenberg, M.; Saltzman, M.Phase I study with selective S1P₁/S1P₅ receptor modulator BAF312 indicates that S1P₁ rather than S1P₃ mediates transient heart rate reduction in humans Mult. Scler. 2009, 15, S31– S150
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Meno-Tetang, G. M. L.; Li, H.; Mis, S.; Pyszczynski, N.; Heining, P.; Lowe, P.; Jusko, W. J.Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses Drug Metab. Dispos. 2006, 34, 1480– 1487
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Brinkmann, V.FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system Br. J. Pharmacol. 2009, 158, 1173– 1182
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Noguchi, K.; Chun, J.Roles for lysophospholipid S1P receptors in multiple sclerosis Crit. Rev. Biochem. Mol. Biol. 2011, 46, 2– 10

2010146105A1	Jun 17, 2010	Dec 23, 2010	Glaxo Group Limited	S1p1 agonists comprising a bicyclic n-containing ring
US8222245	Dec 19, 2008	Jul 17, 2012	Glaxo Group Limited	Oxadiazole derivatives active on sphingosine-1-phosphate (S1P)
US8263620	Dec 19, 2008	Sep 11, 2012	Glaxo Group Limited	Oxadiazole derivatives active on sphingosine-1-phosphate (SIP)
US8329730	Apr 29, 2009	Dec 11, 2012	Glaxo Group Limited	Compounds