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3 3 4 4 5 5 5 5 6 1 1 12 18 25 25 31 31 31 31 32 32 37 43 43 45 48 48 48 48 49 5

1 2 3 4 3

1.56mg.5mg D- 3 15.9mm 5.8mm.96g FTY.5mg FTY.5mg OH NH2 OH H3C HCI 5

7 BCG Torsades de pointes a 2 2

1 5264.6 1 9 8 7 6 5 4 3 36. 2 1 5 48 p.6logistic regression model T2 1 9 8 7 6 5 4 3 2 1 2 18 16 14 12 1 8 6 4 2 4.4 6.1 7. 5 p.4logistic regression model Gd 5 48 MeanSD p.1negative binomial model 2EDSS 1.1

/ 1.4.99.5 1.2 1.8.6.4.2 95CI 57 57.67-1.45.29-.87 p.47 negative binomial model 2 EDSS 1 9 8 7 6 5 4 3 77.1 62.8 2 1 2 4 6 8 1 12 14 16 18 2 log-rank 11

12 1 8 6 4 2 62.2% 89.6% 64.3% 88.3% 89.7% 65.1% 12 24 6 p.1 logistic regression model T2MRI 25 2 15 1 5 24 12 6 MeanSD p.1 negative binomial model 394 367 339 37 41 48

/.6.4.3.4.18.5.2.1 95CI 418 425.34-.47.15-.22 p.1negative binomial model 2EDSS 1 9 8 7 6 5 4 3 2 1 7.4 45.6 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 p.1log-rank 13

24 4 3 2 1 9 18 27 36 45 54 63 72 81 9 p.26 log-rank.5 1 395 383 383 358 357 1.5 2 2.5-3. 6 12 331 MeanSD p.6 p=.26 p.1 rank ANCOVA 14

1 9 9.1% 8 7 6 5 4 3 2 1 429 9 8 7 6 5 4 3 2 1.7 1 372 15 8.8% IFN-1a431 2.6 IFN-1a361 p.1 logistic regression model MeanSD p.4 negative binomial regression 2 EDSS

/.5.3.2.16.33.4.1 429 95CI.12-.21.26-.42 IFN-1a431 p.1negative binomial model 2EDSS 1 9 82.6% 8 7 6 5 4 3 2 1 69.3% IFN-1a 5 1 15 2 25 3 35 p.1log-rank 16

1 1.31.45 2 368 IFN-1a359 MeanSD p.1wilcoxon 17

18 % 161 1487.% 38 % % 7345.3 332.5 2616.1 2113. 212.4 138.1 4528. 85. 85. 53.1 53.1 31.9 31.9 31.9 21.2 21.2 21.2 16.2 63.7 53.1 42.5 42.5 31.9 31.9 21.2 21.2 21.2 148.7 74.3 31.9 21.2 21.2 127.5 74.3 21.2 116.8 53.1 31.9 21.2 31.9 21.2 21.2 21.2 7

19 % % 116.8 95.6 85. 6641. 21.2 31.9 21.2 21.2 31.9 31.9 31.9 4729.2 74.3 42.5 42.5 31.9 21.2 21.2 % 42.5 42.5 31.9 31.9 21.2 21.2 21.2 21.2 31.9 - % 21.2 21.2 21.2 21.2

2 % 2,344 1,51464.6% 3,45 % % 29112.4 154.5 3.1 381.6 2381.2 682.9 17.7 9.4 7.3 3.1 3.1 3.1 381.6 19.8 14.6 1.4 8.3 6.3 3.1 3.1 3.1 291.2 4.2 15.6 15.6 13.6 6.3 4.2 3.1 944. 3413. 3.1 3.1 3.1 3.1 3.1 3.1 114.3 713. 261.1 241. 241. 2.9 17.7 12.5 12.5 7.3 6.3 5.2 4.2 4.2 4.2 4.2 3.1 3.1 3.1 3.1

21 % 21.9 5925.2 532.3 411.7 381.6 361.5 351.5 281.2 241. 231. 15.6 15.6 14.6 12.5 11.5 1.4 1.4 1.4 9.4 9.4 8.3 8.3 8.3 7.3 7.3 7.3 7.3 6.3 6.3 6.3 6.3 6.3 6.3 5.2 5.2 5.2 5.2 4.2 4.2 4.2 3.1 3.1 3.1 % 2421.3 954.1 281.2 261.1 18.8 18.8 1.4 8.3 7.3 7.3 6.3 5.2 5.2 5.2 4.2 3.1 1.4 4.2 4.2 177.3 1164.9 582.5 552.3

22 % 833.5 763.2 763.2 29912.8 251.1 15.6 8.3 7.3 177.3 632.7 18.8 18.8 15.6 6.3 5.2 5.2 5.2 4.2 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 % 231. 5.2 4.2 4.2 562.4 9.4 8.3 5.2 4.2 3.1 17.7 13.6 11.5 11.5 7.3 7.3 5.2

23 % 21.9 16.7 1.4 4.2 3.1 11.5 7.3 4.2 4.2 3.1 3.1 3.1 3.1 813.5 652.8 321.4 18.8 % 11.5 532.3 2361.1 662.8 1.4 8.3 8.3 7.3 6.3 4.2 4.2 3.1 3.1 341.5 261.1 241. 13.6 9.4 9.4 9.4 7.3 5.2 5.2 4.2 3.1 3.1 3.1 3.1 1767.5

24 % % 934. 692.9 4.2 4.2 3.1 3.1 % 56524.1 187.7 1375.8 114.7 773.3 582.5 482. 451.9 231. 22.9 21.9 17.7 17.7 16.7 15.6 15.6 13.6 13.6 12.5 11.5 1.4 8.3 8.3 7.3 6.3 5.2 5.2 5.2 4.2 4.2 4.2 3.1 3.1 3.1 %

ng/ml 5.5 5. 4.5 4. 3.5 3. 2.5 2. 1.5 1..5 MeanSD 1.25mgn=6 2.5mgn=7 5mgn=6 72 144 216 288 36 432 54 576 648 Tmax h Cmax ng/ml AUClast ngh/ml T1/2 days 1.25mgn=6 161636 1.1.2 16827 5.92.4 2.5mgn=7 161636 1.9.3 35387 5.81.5 5mgn=6 161236 3.51.2 823292 7.63.4 1.25mgn=5 6612 1.3.2 85 2.5mgn=7 12612 2.2.3 3716 5mgn=6 12616 3.61.1 15876 MeanSD : 25

1 ng/ml 4.5 4. 7 ng/ml 24 21 MeanSD n=6 3.5 18 3. 2.5 2. 1.5 15 12 9 1. 6.5. 4 8 12 16 2 24 3 4 8 12 16 2 24 Tmax h Cmax ng/ml AUCtau ngh/ml T1/2 days 1 14616 14616 3.1.8 3.71.1 5412 5214 7 12616 9616 18.24.8 11.33.5 38216 23676 7.92. 6.2.4 MeanSD : n=6 26

ng/ml 14 12 1.5mg.5mg 1.25mg 1.25mg 8 6 4 2 1 2 3 4 5 6 MeanSD.5mg 1.25mg.5mg 1.25mg 15 2.641.1 54 6.762.59 54 1.37.61 54 3.61.54 54 1 3.151.3 54 8.12.55 51 1.69.87 54 4.321.52 51 2 2.961.23 52 8.773.8 5 1.57.81 51 4.881.93 5 3 3.191.31 51 8.613.2 49 1.7.86 5 4.81.92 49 6 3.51.44 47 8.923.55 48 1.82.81 47 4.842.9 48 ng/ml 27

ng/ml 2. ng/ml 2. MeanSD n=29 1.5 1.5 1. 1..5.5. 6 12 18 24 3 36 42 48. 6 12 18 24 3 36 42 48 Tmax h Cmax ng/ml AUCinf ngh/ml T1/2 h 161236 361248 1.4.2 1.3.2 27312 269127 14765 14776 668 12616 1.6.3 1..2 12751 a 12756 a 14268 a 14876 a MeanSD : n=29a : n=27 28

ng/ml 1.5 n=9 n=9 ng/ml 1.5 MeanSD n=9 n=9 1. 1..5.5. 6 12 18 24 3 36 42 48. 6 12 18 24 3 36 42 48 Tmax h Cmax ng/ml AUCinf ngh/ml T1/2 h 12648 12136.88.26.65.14 13191 8237 9453 8525 8612 861 1.13.29.9.23 7634 a 6631 a 955 a 1146 a MeanSD : n=9a : n=5 29

ng/ml.8.7.6.5.4.3.2.1 n=8 n=8 n=16 2 4 6 8 1 12 14 ng/ml 1. 1. n=6 n=6.1 2 4 6 8 1 12 14 16 18 2 22 Tmax h Cmax ng/ml AUCinf ngh/ml T1/2 days a 12636.65.12 1539 4.91.7 1mg a 24848.57.1 13145 6.72.5 b 12848.64.17 9125 4.31.5 5mg c c c c 363696 12836 1612 8612 3.71.1 3.4.5 4.51.9 5.41.4 1,326389 63919 179133 191112 1.71.8 7.32.3 MeanSD :, : AUClasta : n=8, b : n=16, c : n=6 3

31 NH2 FTY72 OH HO NH2 FTY72-P (S)-enantiomer(AML629) OH HO HO O O P NH2 M1 OH COOH HO NH2 M2 OH COOH HO NH2 M3 OH COOH HO NH2 M4 OH COOH HO NH2 M12 OH OH HO (not observed) NH +oxygen M29 OH O HO NH -2H2 M27 OH O HO NH M3 OH O HO NH M28 OH O HO COOH NH2 Gluc. M22 OH HO

/mm 3 3, 2, 1,.5mgn57 1.25mgn54 n57.5 15 1 2 3 6 19 cells/l 4 2 7 14 21 28 42 32 n24 n24 56

% 4 3 2 1 1 2 3 4 5 6 7 8 36 52 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 n12 n15 %5 4 3 2 1 1 2 3 4 5 6 7 8 9 n12 n15 4 8 12 16 2 24 28 32 36 4 44 48 52 56 33

1.5mg1 bpm 1 95 9 5mg 5mg 78 78 85 8 n6 n6 75 7 65 6 55 5 45 1 2 4 6 12 18 24 3 36 42 48 54 6 66 72 34

bpmbpm 4 2 2 4 6 8 1 12 14 1.68.53.53.37 1.3 3.9 1.37 4.3 3.83 7.67 7.42 9.2 9.74 9.6 11.79 13.1 13.53 13.49 1 2 3 4 5 6.5mgn57 1.25mgn54 n57 6 4.4 4 3.12 3.2 2.33 1.72 1.81 2 1.32.75.87.54.38.75.29 1.4.46.61.25.5.56 2 1.3 4 3.14 6 8 1 12.5 15 1 2 3 4 5 6.5mgn57 1.25mgn54 n57 35

bpmmean95ci 1 9 8 7 6 5 7 bpm 1 9 8 n12 n13 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 n12 n13 1 n12 n13 1 9 8 7 6 5 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 14 n12 n13 bpm 1 9 8 7 7 6 6 5 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 5 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 2324 36

37 S1P1 S1P G G S1P1 -P -P S1P -P S1P1 nmol/l S1P1 nmol/l Th17Th1 S1P1 nmol/l S1P1 Th17Th1 S1P1 -P S1P1 nmol/l S1P1 nmol/l S1P1 nmol/l S1P1

S1P S1P1 S1P2 S1P3 S1P4 S1P5 1 1 1 1 1.3 218 1 1 3.1 28.9.6 8.1.3 1 6 4 2 % % % 1.5 2 2 8.1 1 16 16 Control 1 2 1 3 1 4 1 5.5.1 1. 12 8 4 12 8 4.5.1 1. S1P1 mg/kg 39

7 14 21 28 MeanSD 3. 3. rm-ifn 2.5 2.5 2. 2. 1.5 1.5 1..5 1..5 ## ## 7 14 21 28 1 8 6 4 2 7 14 21 28 7 14 21 28.1mg/kg.3mg/kg rm-ifn 3 IU/ rm-ifn 1 IU/ n=12 : p<.5: p<.1vs Steel : p<.1vs ##: p<.1 vs rm-ifn 3 IUWilcoxon : p<.5: p<.1 vs rm-ifn 1 IUWilcoxon 4

3.5 3. 2.5 2. 1.5 1..5 11 1228 5 1 15 2 25 3 453 35 4 45 5 55 : p.1tukey test AD HE BCE 41

EAE EAE EAE EAE EAE EAE 42

13Hz 35-36C 151ng/mL herghek239 herg 1255ng/mL 25ng/mL 5ng/mL herghek239 herg 352C.5mol/L 2ng/mL 2.5mol/LhERG 25% herghek239 1 herg 352C AML629.31mol/L 14ng/mL 1mol/L.4mol/L herg18%.3.1.31mol/l 1.334.413.2 343.9ng/mL 3 1GLP 2 3343.93 AML629 : FTY72S- 43

44 11.1131.111 113 11.111.111.1131 1 1 1 ph 3 1 4 3 3 1 1 8 3mg/kg 1mg/kg 1mg/kg 1mg/kg-21.7 +33.3SBP T 3mg/kg 1mg/kg-29% 3mg/kg 1mg/kg.111 Irwin 4.111 1.111 1.111 1.111 5.111 2 mg/kg 1 SBP :

mg/kg mg/kg 5 1255 1 5 5 1255 1 25 5 361 1 3 1 12 1 >2 1 : mg/kg/ mg/kg/ 13 1.1.55.5 4 1.3.1.33136 1.3 13 26 1 12.1.55.1.3.31 1.1.3 27 2.31.57.5.3 2 12 361 1 3 4 3.1.1.11313 1.1 26 4.1.111 1.1 2 2 313 1 3 13 43 3 4 131 1.53 1 1.5 52 4 131 1 1 1 : 45

2 mg/kg/ 131 1 mg/kg/ 1 1 2 131 1 1 <1 2.3.1.3 1.3.3 7.1.3.33 1 7 136 1 2.51.55 1.5.5 25.5.15.5 1.15 <.5 1.55 1 : : 46

25/6%RH PTP 36 3/65%RH PTP 12 4/75%RH PTP 6 5 PTP 1 12luxh2Wh/m 2 ICHQ1AR21563631Q1B9528422 48

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