‘é'l D9535)?
`
`
`
`lb???
`NO... 1
`v.2;
`C.Ol*—--'—'--"5E{J: 9314sinUOU
`Tl: DRUGS 0F 'I‘HI‘.‘ FUTURE
`
`fire}??-
`
`uumuuum
`
`.n,
`
`:mn 2
`uary
`
`.2:
`
`D!-
`*0
`
`MD\
`
`—
`‘—
`
`ND
`
`“9
`
`Apotex v. Novartis
`lPR2017-00854
`
`NOVARTIS 2061
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2061
`
`1/9
`
`

`

`Drugs
`Of the
`
`
`FUture Volume 22, Number 1, 1997'
`
`Contents
`
`Monographs
`
`l1
`18
`93
`30
`'34
`38
`40
`
`fi-Aminolevulinic Acid. Pnorodynami’c therapy Aniioeoplasiio. Agenr for aoiinr’o keratoses. Antiaooe. J.T. Panto
`FTY720. lmmunosuppressant. K. Chiba, K. Adachi
`lganidipine Hydrochloride. Calcium channel blocker. C.P. Robinson. K.A. Robinson. .J. Castafier
`Nibentan. Anriarrhyl‘hmio. RG. Glushkov. MD. Mashkovski. S.D. Yuzhakov
`ST-899. Treatment for endotoxic shook PAF antagonis!‘ V. Ruggiero et al.
`TEX-710. Am‘fneoplasrio. Platinum complex. A. Hoshi. J. Castafier
`VP-63843. Antiviral. FLA. Fromtling. J. Castafier
`
`Review Articles
`45
`Modulators of plasminogen aclivator inhibitor-1 {PM-1) activity
`P. Charlton
`'
`
`53
`
`Novel oliVacine and elliplicine derivatives: 3-18020-2 and related compounds as potential anlitumor agents
`A. Pierre. G. Arassi. M. Dew'ssaguef. Er stagni'
`
`Information Update 1-20
`62
`AD-5423
`52
`Alovirsen Sodium
`62
`Alkasar-1B
`62
`Anastrozole
`63
`Aranidioine
`64
`Artemisinin
`65
`Atovlrdine Mesylate
`65
`ETA-243
`66
`Cisairaourium Besilate
`6?
`Colestimide
`68
`Colfors'rn
`71
`Cyslemustine
`71
`Decitabine
`?2
`Dexmedetomldine
`73
`Didemnin B
`74
`Didox
`74
`E2020
`75
`Edobacornab
`7'5
`Famotidine
`76
`Fazarabine
`75
`Fenoldopam Mesylaie
`Y7
`FK-409
`7?
`Flesinoxan Hydrochloride
`78
`Fluoxetine Hydrochloride
`78
`(38-522
`
`79
`79
`81
`81
`B1
`62
`B2
`83
`83
`84
`35
`85
`90
`91
`91
`92
`93
`94
`95
`95
`95
`96
`95
`97
`97
`
`HG P—SD
`lbandronic Acud Monosodium Salt Monohydraie
`loxilan
`Loxiglumide
`Mildronete
`Milnacipran Hydrochloride
`Naltopidil
`Nebracelam Fumarate
`Nefiracelam
`Ondanselron Hydrochloride
`Olenzepad
`Paclitaxel
`PEG-Hemoglobin
`Rabeprazole Sodium
`Ramoselron Hydrochloride
`Rolipram
`Roquinimex
`Sebriplalin
`Sumatriptan Sucoinale
`Suritozole
`\i'AQ'l’ATM
`Zaleplon
`Zaprinast
`Zenareslal
`Zopolreslal
`
`2/9
`
`2/9
`
`

`

`Drugs
`of the
`Future
`
`Editor: J.Fi. Prous
`Chemical Editorial Stair: J. Castaner, RM. Castafier. J. Prous. Jr.
`Editorial Statl: P. Leeson. A. Graul. N. Meaty. X. Rabasseda
`Database Manager: Ft. Atentorn
`
`Contributing Editors
`M. Acou—Gharbie (USA). L. de Angelic {Italy}. VP. Arya (India), E. de Clercq (Belgium). [5. Eastland (USA), J. Engel (Germanyi, C.J. Fowler
`{Sweden}, FLA. Fromtiing (USA). J. GarciavFlalaneil (Spain). Fifi. Gtushkov (Russia). SJ Hopkins {UK} , A. Hoshi (Japan). H. Koch (AUSI‘!3}'
`SK. Kulkarni (indie). G. Leciorc (France), W. Lcscher {Germany}. Fl. Mannhoid (Germany). M. Neuman (France). M. Nikotova {Bulgaflair
`M. Nogradi {Hungary}. BM. Paton (Canada). J.T. Panto (USA). M. Protiva {Czech Hop]. 5. Flédl (Crash Rep). V. Hejholec (Czech FtePJ‘
`C.P. Robinson {USA}, J. Fluyun {China}, .J.T. Xie (China). R.K.Y. Zoe-Chang (USA)
`
`Drugs oi the Future is a monthly publication designed to provide In monograph form inion-nation on new drugs from their WE!
`phases of development up to their marketing.
`
`An Information Update section appears monthly providing the most recent information available on drugs whose monographs
`were Published in the same-n umbered issue of previous volumes. Drug information in this section can be consulted by devel-
`opmental phase or alphabetical order.
`
`Articles on topical fields. presented by leading specialists, explore the innovative areas of drug research and highlight the
`mechanisms by which drugs act, relating chemical structures to specific bioiogical activities.
`_—_____—__.__—.——_—-————————-—-—-'—
`
`3/9
`
`3/9
`
`

`

`Drugs
`of the
`Future
`
`Drugs oi the Future is published monthly. A pharmacostructural index appears annually in the December issue. ()umuliilWe
`Chemical formula and general indices are published separately and mailed to sbbscribers in January.
`
`Subscription Rates
`
`Calendar year subscription price for Volume 22. 1997 is US $ 975. Airmail additional (optional): America it 70. Asia 3 12_0.
`E'Jfflpe S 40.Back volumes are available in book iorm. offering an Encyclopedia of drugs in various stages of research, contin-
`uously updated as new information becomes available.
`
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`Remittances and orders for subscriptions. notices of change of address. claims for missing numbers and requests for saint?"e
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`indicate the code number from mailing labels in all correspondence relating to your subscription.
`
`Computerized Databases
`
`CIPSLINE no”. a series of structural databases, are available for use with Molecular Design Ltd.'s graphic chemical data
`management system for personal computer ChemBase‘”. These databases comprise drugs selected item Drugs of the
`Film"? and Drug Data Report.
`
`Online and CD-ROM versions 01 Drugs of the Future are available For more information contact Prous Science Oniine Publi-
`cations
`
`Authorization to photocopy items lor internal or personal use, or the internal use of specific clients, is granted by JR. Pious. 5A.. for users
`registered with theI Copyright Clearance Center {CCCJ Transactional Reporting Service. For those organizations that have been granted a
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`COPWI'ght 1997. J. Ft. Prous. SA. Publishers. Reproduction in whole or part is not permitted except by written permission from the publisher.
`
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`APP Publicallon not suoinot to mandatory control at circulation because advertising page: on; less than 10% o! the total numberoi pages.
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`
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`ISSN' 03?:M3232 — Deposits Legal EH. tat-1.975 - anlocl in Spain. - COMGHAFIGINUUGHAF - Barcelona
`
`4/9
`
`4/9
`
`

`

`Drugs ot the Fulure199?.22l1ji: tit-22
`Copyright PHOUS SCIENCE
`
`
`
`FTY720
`
`immunosuppressant
`
`2—Amino-2-[2-l4-octylphenyl)ethyll-‘t.3-propanediol hydrochloride
`
`
`H36
`
`H0
`
`””2
`on
`
`t-ICT
`
`Moi wt: 343.94
`CIQH33N02.HCI
`-—._.__._____—_
`
`CAS: 162359-56-0
`
`EN: 210392
`
`Synthesis
`
`_The Friedel-Cratts condensation of phenethyl acetate (It
`with octanoyt chloride (It) by means at AICI3 in dichloroe—
`mane elves 2-(4-octanoylphenyilethyl acetate (ill). which is
`reduced with triethytsliane in TFA to afford 2-f4-octylphe'
`nytlethyl acetate {IV}. The deprotection of (IV) with sodium
`ethoxide in ethanol gives 2—f4—octylphenyl)ethanoi
`(V).
`which is treated with methanesulionyl chloride followed by
`sodium iodide in refluxing 2-butanone yielding 2-(4-octyl-
`phenyllethyl iodide (VI). The condensation of (VI) with di-
`FthIacetamidomalonate (VII) by means of sodium ethox-
`rde in ethanoliTHF gives dlethyl 2-acetamido-2-[2-{4-octyl-
`Phenyllethyumalonare (VIII). which is reduced with LiAlHq
`in THF and treated with acetic anhydride in pyridine to afford
`2 - acetamido ~ 2 - {acetoxymethyl} - 4 - f4 - octylphenyll-
`PUlYl acetatele).The hydrolysisofle)withlithiurn hydrox—
`ide In refluxing methanoirwater gives 2-amino-2—[2-(4—ocwl-
`Phenyllalhyllpl'opane-l.S-diol (X). which is finally treated
`with HCI in diethyl ether (1. 2). Scheme 1.
`
`Description
`
`White crystalline powder. m.p. about 26-3 ”C (decomDJ-
`
`Introduction
`
`sible to elucidate the mechanism of immune response at
`cellular and molecular levels. During the research on immu-
`noregulatory mechanism. cyclosporin A {05A}, a fungus
`cyclic peptide from fir‘choderrna pofysponrm, was found to
`suppress immune responses by inhibiting production of
`interleukin-2 {lL-2) in antigen-stimulated helper T-cells [3.
`4}. Since its first clinical use as an lmmunosuppressant,
`CsA has contributed greatly in preventing acute rejection in
`human organ transplantations. Recently. tacrofimus (TRL,
`F K505). a novel macrolide from Streptomyces tsukubaen-
`sis, was reported to have 10- to too-told more potent immu-
`nosuppressive activity than CsA (5-7). Similar to CsA, TFlL
`inhibits antigen-inducedT—cell proliferation by inhibiting lL-2
`production in helper T-cells. Although CsA and TFtL bind to
`different proteins, termed cyclophilin and FKBP, respec-
`tively. both cyclophilinICsA and FKBPr'TFiL complexes
`inhibit phosphatase activity of calcineurin which activates
`nuclear factor in activated T-ceils (NF-AT} involved in the
`promotion at IL-2 genetranscn'ption {8). Since CsA and TFtL
`have almost the same mechanism of action, these drugs
`Show quite similar side effects. such as renal and liver toxici-
`lies {9). CsA- or TFtL-based multiple drug therapy with ste-
`roids or other immuncsuppressants such as azathioprine
`and mizoribine is widely used in order to reduce the side
`effects of individual immunosuppressants in human organ
`transplantations {10, 11). However, the concomitant use of
`05A and TFiL is contraindicated because of their similar
`side eftects based on the mechanism at action. Thus. a
`novel immunosuppressant should not only be highly safe
`but also possess a mechanism of action distinct from Us“.
`and TFtL in order to allow concomitant administration with
`them.
`
`Forthe above reasons. Yoshitomi Pharmaceutical Indus-
`tries Ltd. began research on immunosuppressive sub-
`stances from the products of vegetative wasp with Profes-
`Sor‘ Tetsuro Fujita of Kyoto University (currently, Profesor of
`Setsunan University) and Taito Co.. Ltd. In the culture broth
`at isarr'a sinclairii. we isolated myriocin (ISP~|] and myces-
`tericins, which have a potent immuncsuppressive activity in
`vitro [1 2. 13). Chemical modification ofmyrlocin (12-14) led
`to a synthetic compound. 2-amino-Q-[Q-{ti-octylphenylt-
`ethyiipropane-i .S—diol hydrochloride (FTY720) (2) that has
`more potent immunosuppressive activity and less toxicity
`compared to myriocin (1, 2, 14-16).
`
`
`With the remarkable progress in immunology including
`the discovery of various cytokines. T~cell receptors and
`fntercellular adhesion molecules. it has now become pos-
`
`Kenjl Chiba. Kunitomo Adachi. Research Laboratories. Yoshi-
`tomr Pharmaceutical Industries. Ltd. 3-7—25 Koyata. iruma-shi.
`Saitama 358‘ Japan.
`
`5/9
`
`5/9
`
`

`

`Drugs Fut 199?‘ 22(1)
`
`19
`
`Scheme 1: Synthesis of mm
`
`NCIS
`—_—&
`ct
`“3‘6”sz
`0
`llll
`
`0
`
`till:
`
`CH CH
`3‘
`
`at
`
`0E1
`
`DEI
`
`Clthtlgly
`
`[Will
`
`€— _._
`NaDEIrEiOH
`THF
`
`mam”???
`
`one
`
`E15 Sill
`—-%
`TFA
`CHsicnzty
`
`'
`
`iiMsCI
`E at Hal
`
`crrmcnm
`
`mosri
`
`OH
`
`Wt
`
`tV)
`
`ill-l
`
`i} UN Hg
`2) MgOiPyr
`
`NI lM
`on: LiOIl
`
`AcO
`
`t1?“
`
`custom,
`
`"0
`
`NH;
`0“
`
`llCIi'ElQO
`
`E
`CliaiCHzt-y
`
`H0
`
`N‘ltgOH
`
`.lrlCI
`
`CH3rCH i
`27
`
`Pharmacological Actions
`
`In major histocompatlbility complex {MHCJ-incompatible
`rat strains of WKAH donor (FtTtki and F344 recipients
`{RT1JV‘}. all skin grafts in the control (vehicle-treated) group
`were rejected in 6-7 days after transplantation. FTY720 sig—
`nificantly prolonged graft survival at an oral dose of 0.1
`mgikg or more in a dose—dependent manner {1 7). Adminis-
`tration of FTY720 at an oral dose of 10 mgi‘kg for 14 days
`resulted in a prolongation of graft survival with median sur-
`vival time (MST) of 27.0 days without renal toxicity or other
`toxic signs. 65A and TRL were also effective at oral doses
`of 3 mgikg or more and 0.3 mgl'kg or more. respectively, in
`this model. Fourteen days-repeated administration of (35A
`at 100 mgikg or TRL at 10 mgikg resulted in a prolongation
`of graft survival with MST of 26.0 days and 225 days.
`respectively. However, 1 of 8 recipients died within the
`course of administration of CSA at 100 mgikg. These lind-
`ings indicate that FI'Y720 prolongs the skin allogratt sur-
`vival acrosa a Mi—lC barrier and is more potent than (35A or
`TFlL.
`
`In clinical organ transplantations, CsA-based combina-
`tion therapy with prednisolone or other immunosuppres-
`sants is widely used in order to reduce the side effects of
`individual drugs [10, 11). Therefore. itis importantto investi-
`gate whether combined use ol FTY720 and CsA produces
`antagonistic. additive or synergistic eifecl on experimental
`attogratt models. The concomitant effect was evaluated for
`Fit/720 combined with (35A in the MHC-incompatible rat
`skin allograft model. In comparison with therapy of either
`FI'Y720 or CsA alone, the combined administration of
`FTY720 with CsA at 3 mgfirg or 1 0 mgi'kg resulted in a signif-
`icant prolongation of skin allogralf survival. in combination
`with CsA at 10 mglkg. FTY720 even at a dose of 0.1 mglkg
`
`remarkably prolonged allograit survival with MST of more
`than 70 days in 5 out of B recipient rats. The values of com-
`bination index. which Were calculated by the method of
`Kahan etal. (18L were less than 0.1 by combined adminis—
`tration of FTY720 with CsA‘ indicating a synergistic effect.
`From the results of combination therapy earperlrnents. it is
`suggested that FI‘Y720 acts synergistically with CsA. A
`similar synergistic effect was obtained in combination ther-
`apy of FTY720 and TFlL in this model. in MHC—oornpatibfs
`rat strains of LEW donor and F344 recipient, FI'Y720 at
`0.03 mglkg or more also significantly prolonged the Survival
`of skin allograft and showed a synergistic effect on pro-
`longation of allogralt survival in combination With USA at 3
`mgr’kg.
`The effects of FTY?20 on heterotopic cardiac allograft
`survival was compared with those of (35A and TFlL by using
`WKAH donors tFtTtk] and Act recipients {FiTtaV‘} in rats
`[19). All cardiac altcgrafts in the control (vehicle-treated)
`group Were rejected within 14 days (MST: 12.0 days) after
`transplantation. Treatment with FTY720 at an oral dose of
`0.1 mgiirg or more significantly prolonged cardiac allogratt
`survival. The MST of FTY720 administration with 0.1. 0.3,
`1,3 and 10 mglkg for 14 days were 20.0. 21.0. 25.5. 29.5
`and 58.5 days. respectively. FTY72D at 10 mgikg induced
`a long-term graft survival for more than 100 days in 3 out of
`8 recipient rats. 05A and TRL significantly prolonged car-
`diac allogralt survival at doses oi 10 mglkg or more and 1
`mgikg or more. respectively. However. these drugs barely
`induced long-term grail survival even at the highest dose
`tested. These results suggest that FTYYED is more potent
`than (35A or TFlL in rat cardiac allograft and that this com-
`pound is capable of inducing long-term graft acceptance in
`vascularized organ transplantations. FTY720 at an oral
`
`6/9
`
`6/9
`
`

`

`Table l: Comparison of pharmacological activities of Fl'Y?20. 05A and int.
`
`FTY720
`
`
`
` Response suppressed Species FTY720 CsA TFIL
`
`
`
`
`
`
`
`in vivo too.)
`
`allograit rejection
`
`Combination with Gen
`
`Combination with TFIL
`
`GvHR
`
`DTH Wet-ISA)
`Antibody production [to SRBC}
`Adiuvantinduced arthritis
`Collagen-induced arthritis
`EAE
`
`Decrease in number of peripheral blood lymphocwes
`
`in ultra
`
`lL-2 production
`
`lL-2 mRNA expression
`
`Flat {skint
`Flat {heart}
`Flat (skin)
`Flat theartl
`Dog
`(Kidney)
`
`Rat (skin)
`Fiat (heart)
`
`Hat
`
`Mouse
`Flat
`Hat
`Flat
`Hat
`
`Flat
`Dog
`Monkey
`
`Flat
`
`Flat
`
`0.1 mglkg
`01 mgfl-(g
`0.1 mglkg
`0.1 mgiltg
`0.03 mgrkg
`
`01 mgllrg
`0.1 mglkg
`
`0.1 mqu
`
`0.03 mglkg
`0.1 mgllrg
`0.1 mgrkg
`01 mgflrg
`0.1 mgrkg
`
`0‘1 MEWS
`0.03 mgl'l-rg
`0.1 mglkg
`
`> 1000 mm
`
`2~ 1000 nM
`
`3 mgi’ltg
`3 mgr‘kg
`
`0.3 mgr‘kg
`0.3 mgl'lrg
`
`3 mgikg
`
`-
`
`3 mglkg
`3 mglkg
`3 mgllrg
`3 mgi’lcg
`10 "1911th
`
`‘
`-
`.
`
`.
`0:3 mgllrg
`-
`-
`_
`
`‘
`.
`
`10 ntlit
`
`10 nM
`
`0.1 I'IM
`
`01 [11111
`
`65A: cyclcsporln A; TFlL- lacrolimus: GvHFl: grail versus host reaction; 0TH: delayed—type hypersensitivity: MeHSA: methylated human
`serum albumin; SFIBC: sheep red blood cells: EAE: experimental allergic oncephalomyelitis; lL‘2: interleukin 2.
`
`dose of 0.1 mglltg or more signilicantly prolonged allograft
`survival
`in
`combination with Call
`at
`3 mgl'lrg as
`compared to the treatment with either FI'Y720 or CsA
`alone. Fl'Y720. when concomitantly administered with
`Gen. produced indefinite graft survival in more than 50% of
`recipients. FTY720 at an oral dose of 1 mglkg combined
`with TFlL at a dose of 1 mgilrg also showed a synergistic
`effect on graft survival in this model. These results indicate
`that treatment with FTY720 concomitantly administered
`with 05A or TRL synergistlcally prolongs graft survival and
`Induces indefinite allogratt acceptance more frequently
`than FTY720 alone in rat cardiac allogralt model.
`In canine renal allograft. either azathioprlne or mlzoribine
`in combination with CsA was reported to show a significant
`prolongation of graft survival as compared with each drug
`alone (20. 21). The effect of FI'Y720 in combination with
`CsA on renal allogralt survival was investigated in dogs by
`using mongrel donors and beagle recipients (22-24). in the
`control {vehicle-treated) group. levels of serum creatinine
`were irreversibly elevated within 10 days. and all animals
`died within 17 days due to renal dystunction by acute rejec-
`tion. The levels of serum creatinine were also elevated
`within 14 days in the 5 mgtkg FI'Y720- and 10 mglkg Cert.
`treated groups. With combination of FTY?20 and 05A. the
`serum creatinine levels in 4 out of 5 recipients were main—
`
`tained at normal for at least 30 days alter transplantation.
`MST in the control allograft group was 9.0 days. Treatment
`with FTY'r‘20 at 5 mglkg or Gan at 10 rngikg resulted in
`slight. but not significant. prolongation of graft survival
`(MST: FTY?20-treated group: 12.0 days. CsA-treated
`group: 11.0 days). Combination treatment with FTY720 at
`5 mglkg and 05A at 10 mgl'ltg resulted in a significant pro-
`longation oi grail survival with MST of 74.0 days. FI'Y720
`at lower doses {0.1-3 mgikg) also significantly prolonged
`renal allograft survival in combination with CsA at 10 mgrkg
`and there were no severe toxic signs in kidney and liver
`function. With the combination treatment of FTY720 with
`(felt. the blood concentrations of unchanged FI'Y720 and
`CsA were not affected by each other. These results suggest
`that FTY720 acts synergistically in combination with Ca“. in
`canine renal allograft model.
`When spleen cells from LEW rats were injected into the
`loot pad of (LEW x BN) F1 rats, the Weight of poptiteal lymph
`node increased to the maximal after 7 days. FTY720 and
`03A significantly inhibited the enlargement in popliteal
`lymph node at doses of 0.1 mgr‘lrg or more and of 3 mglkg
`or more. respectively. in a dose-dependent manner {25).
`Thus.
`the lmmunosuppressive activity of FTY720 was
`30~lold more potent than that of CSA in local GvHR in rats.
`FTY720 also prevented the lethal GvHFl caused by intrave-
`
`7/9
`
`7/9
`
`

`

`Drugs Fut199?.22{1}
`
`2!
`
`nous injection of splenic lymphocytes from LEW donor
`rats into cyclophosphamids-pretreated (LEW x BN}F1
`recipients {25}. In the control {vehicle-treated} group. all rats
`developed severe thHFt-associated symptoms including
`redness of skin and hair loss within 15 days after the Injec-
`tion of LEW spleen cells and died with MST of 22.0 days.
`CsA at a dose of 10 mglkg for 30 days significantly pro—
`longed survival ofthe recipient rats. However, withdrawalof
`CsA caused severe symptoms of le-lFt and subsequently
`all recipients died within 42 days (MST: 40.0 days). Oral
`administration of FTY720 at a dose of 0.1 mgikg for 30 days
`prevented the development of GvHFt-associated symp-
`toms and significantly prolonged host survival (MST: 50.0
`days). Treatment with FI'Y720 at a dose of 0.3 rngiltg
`induced survival for more than 60 days in 4 out of 5 rats with—
`out GvHFl-assoclated symptoms. Treatment with W720
`induced long-lasting unresponsiveness at low doses (01 to
`0.3 mglkg} in the lethal GvHH model. indicating complete
`prevention of GvHFl.
`FTY720 significantly inhibited methylated human serum
`albumin-induced delayed~type hypersensitivity in a dose-
`dependent manner at an oral dose of 0.03 mgrlrg or more
`in BALBic mice. FTY720 completely inhibited joint destruc»
`tion as well as paw edema in adjuvant-induced and type It
`collagen-induced arthritis at an oral dose of 0.1 mgikg or
`more in rats. In myelin basic protein-induced experimental
`allergic encephalomyelitis,
`this compound completely
`inhibited paralysis at an oral dose of 0.1 mgikg or more in
`rats. These results suggest that FTY720 is effective in the
`treatment of rheumatoid arthritis, multiple sclerosis and
`other autoimmune diseases (26].
`
`Mechanism of Action
`
`CsA and TRL were reported to inhibit lL-2 production and
`tL-2 mHNA expression in antigen or mitogen-stimulated
`helper T-cells (6. a). The effect of FTY720 on alloantigen-
`induced lL-2 mFl NA expression was examined in compari-
`son with those ot CsA and TFtL in allogeneic mixed lympho-
`cyte cultures using splenic T-cells of F344 rats as responder
`cells and mitomycin C-pretreated WKAH rat spleen cells as
`stimutator cells. CsA and TFtt. completely inhibited lL.-2
`mFtNA expression at 100 nl’vl or more and 1 nM or more.
`respectively. On the contrary. FTY720 did not affect lL-2
`mFtNA expression at a concentration up to 1000 mm. In the
`same concentration range, FTY720 did not inhibit the pro
`duction of lL-2 by alloantigen- or concanavalin tit-stimulated
`lymphocytes in rats (1 7. 27}. These results indicate that the
`mechanism by which FTY720 suppresses
`immune
`responses to alloantigen is not inhibition of lL—2 production
`from helper T-cetls. Rather. it is presumed that FTY720. in
`combination with CsA or TFtL. shows a synergistic eflect on
`allograft survival because of its distinct mechanism of
`action from 03A and TFlL.
`Contents of lymphocytes in peripheral blood and spleen
`of FTY720-treated intact or allogratted rats were analyzed
`by two-color flow cytometry using anti-rat CD3 and anti-rat
`CD45FiA or NB monoclonal antibodies (17. 27). The num-
`bers of ODS-positive T-cells and CD45FtA or RIB-positive
`B-cells in peripheral blood were dramatically decreased
`within 6 h after oral administration of FI'Y72O at doses of
`
`0.1-10 mgikg. In dogs. monkeys and rats. oral administra—
`tion with FTY72D also decreased lhe number of circulating
`lymphocytes in peripheral blood. Especially remarkable
`was the reduction in the number of T-cells. Withdrawal of
`FTY720 treatment caused the number of lymphocytes in
`peripheral blood to return to normal levels within 2 weeks.
`FTY720 also induced a decrease in the number of T-cells
`and B-cetls in spleen. thoracic duct and peripheral blood.
`while the number of T-celis and B-cells in mesenten’c and
`peripheral
`lymph nodes were significantly increased.
`FTY720 did not affect the numberot bone marrow cells. thy-
`mocyles and polymorphonuclear cells. Recently.
`it was
`shown that decrease of the circulating lymphocytes by
`FTY720 is due to the acceleration of lymphocyte homing to
`mesenteric and peripheral
`lymph nodes and Peyer's
`patches. The lymphocyte homing was reported to be
`mediated via the lymphocyte homing receptor. including
`L-selectin {CD62L} and Hal}; integrin (CD49drB?) (28, 29}.
`L—selectin and “45? integrin bind GlyCAfv‘l-t and Med-
`CAM-l. respectively. both of which are expressed on cell
`surface of the high endothelial venules (HEV) in lymph
`nodes and Peyer‘s patches (30. 31). Therefore. we pre-
`sume that FTY720 shows immunosuppressive activity by
`sequestration of immunologically competent lymphocytes
`to lymph nodes and Peyer‘s patches and that FTY720
`affects the adhesion between lymphocytes and HEV. Fur-
`ther investigation is necessary to clarify the detailed molec-
`ular mechanism of FTY720.
`
`Conclusions
`
`immunosuppressant. dose-depen-
`FTY720. a potent
`dently prevented acute rejection in experimental allograft
`models. The combination treatment of F-TY720 with CsA or
`TFtL showed a synergistic effect on the prevention of acute
`rejection without enhancing toxic signs of the drugS con-
`comitantly administered in these experimental allograft
`models. Unlike 03A or TFiL. FTY720 did not inhibit the
`expression of lL-2 mFtNA and production of lL-z in alloanti-
`gen-stimulated T-cells. FTY720 remarkably decreased the
`number of circulating lymphocytes. especially T-cells.
`to
`peripheral blood ol rats. dogs and monkeys. and alrophled
`T-cell region in the spleen in viva. On the contrary. lympho-
`cyte homing to lymph nodes and Peyer‘s patches was
`accelerated with FFY720 administration. The immuno-
`suppressive activity of FTY72O is suggested to be due to
`sequestration of immunologically competentT—cells to HEV
`in lymph nodes and Peyer's patches. Thus, FTY720 pos-
`sesses a unique mechanism of action distinct from CsA and
`THL. Based on the results of preclinical studies. concom-
`itant administration of FTY720 with 05A or TFtL is expected
`to prevent acute rejection synergistically without enhancing
`the side effects of individual drugs in human organ trans-
`plantations.
`
`Manufacturers
`
`Yoshitorni Pharmaceutical industries, Ltd. (JP); Taito Co.
`Ltd. (JP).
`
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`

`

`References
`
`1. Fujita. T.. Sasaki. 5.. Yonota. M. Mishina. T.. Adeohi, K.. Chiba.
`K. (Yoshitomi Pharm. ino.. Lto.. Taito Co. Ltd). 2-Amino-t.3-pro-
`panedioi compound and immunosuppressant. EP 627406. JP
`94509345. W0 9408943.
`9. Adachi. K.. Kohara.‘l'..Nakao. N..t\rite. M. CI11ba.t(. Mishine.
`T.. Sasaki. 5., Fujita. T Design. synthesis. and structure activity
`retaiionships oi 2-substituted‘2-amino—i.3-pmpanedioi3: Discou—
`ery of a novei immunosuppressant. FTYi'zo. Bioorg Med Chem
`Lett 1995. 5: 853-6.
`
`:1. Borel. J.F.. Feurer. C., Gublor. H.U.. Stahetin, H. the bioiogicat
`effects of cyciospon‘n A: A new antiiyinphooytic agent. Agents
`Actions 1975. 13:458-115.
`
`4. Borei. J.F.. Phannaooiogy oi oyctospon‘no (Sendimmunei iii.
`Pharmawiogicai properties in vivo. Phannecol Flcv 1989. 41'.
`259—31”.
`
`5. Kim). T.. Hatanaka. H.. Hashimoto. M.. Nishiyams. M. Goto. T..
`Okuhara, M.. Kohsaka. M. Aoki. H.. imanaka. H. FK-5ot3. a novei
`immunosuppressant isoiatod irom a Streptomyoes. i. Fermenta-
`tion. isotettbn. andphysioo-chemiooi and oioiogioai characteristics.
`J Antibiol 198?. 40; 1249435.
`
`5. Kine. T.. Hatanaka. H.. Miyata. S.. lnamura. N.. Nishiyarne. M..
`Yajirna. T.. Golo. T.. Okuhara. M. Kohsaka. M.. Aoki. H.. Ochiai. T.
`KF-SOB. a noveiimmunosuppreseantisototedirom o Streptomyoes
`it. immunosuppressive effect of Fit-506 in vitro. J Antibiotics 1 98?.
`40: 1256-65.
`
`7. Inarn ura. N.. Nakahara. K.. Kim. 1'. . Goto. T.. Aoki. H.. Yarn ag u-
`chi. 1.. Ko hsaka. M.. Ochiai. T. Protongation oistcin oiiograitsurvivai
`in rats bya no veiimmunosuppressive agent. Fit-506. Transplante-
`11011 1938. 45: 205—9.
`
`8. Liu. J.. Farmer. JD. Jr., Lane. W.S.. Friedman. J.. Weissman. |..
`Schreiber. S. L. Caicineurin is a common targetoioyoiopnitin-cycio-
`spoon A and FKEF-FKSOS compioxes. Cell 1991 . 66: 307-1 5.
`9. European FKSUB Multioentre Liver Study Group. Randomised
`tn‘ai comparing tacroiimus (FKStZ-‘oj and oyciosparin in prevention at
`iiuer etiogratt rejection. Lancet 1994, 344: 423-8.
`
`10. Slapak . M.. Geoghagen. T.. Digero‘. N. et at. The use oiciciospO-
`tine in combination with azathioprine and steroids in renai trans-
`piantetion. Transplant Proc 1985. 1?: 1222-6.
`11. Kokado. Y.. lshlbashi. M.. Jiang. H.. Takahara. 8.. Sol-lode. T.
`Low-dose cioiosponn. mizoribtne. andpmdnisotone in most trans—
`piantation: A new tripte‘drug therapy. Clin Transplant 1991). 4:
`1914‘.
`
`12. Fuiiia.T.. Inoue. K.. Yamamoto. 5.. Ikumoto, T.. Sasaki.'S.. Toy-
`ama. H.. Chiba. K.. Hoshino. Y.. Okumoto. T. Fungeimetaboiites.
`Part 11. A potent immunosupprossive activity tound in tsarie sinct-
`airii metaboiile. J Antibiot 1994. 4?; 208-15.
`
`15. Sasaki. S..Hasi1imolo. H.. Kiuohi. M.. lnoue. K.. lkumoto. T..
`Hrroso. H.. Chiba. K.. Hoshlno. Y.. Okumolo. T.. Fujita. T. Fungat
`metahotites. Port 1‘4. Nouet potent immunosuppressants, mitt-‘95“
`teriotns. produced by Myoeria steriiib. J Antibioi 1994. 4?: 42121-33.
`14. Fujita. T.. lnoue. K.. Yamamoto. 3.. Ikumoto. T.. Sasaki. 8.. Toy—
`arna. H.. Yonela. M.. Chiba. K.. Hoshino. Y.. Okumoto. T. Fungai
`metaboiites. Part 12. Potentimmunosuppressant. t-t-deoxomyn‘o-
`oin.
`{23.3H.4Ft)-(E)-2—amino—3.d-dihydroxy-z-hydroxymethyiei-
`oos-E—enoic acid and structure-activity reintionships of myriocin
`derivatives. J Antibiot 1994, 47: 216-24.
`15. Fujita. T.. Yoneda. NL. Hiroso. H.. Basal-ii. 8.. Inoue. K.. Kiuchi.
`M.. Hirase. 8.. Ada-chi. K.. Ante. 11.1.. Chiba. K. Simpte compounds.
`E-aiiryt-E-amino-1.3-propsnediois have potent immunosupprss-
`sire activity Bioorg Med Chem L911 1995. 5: 847-52.
`15. Fuiita. T.. Hirose. H.. Yonets. M. Sasaki. 5.. lnoue. K.. Kiucni.
`M.. Hitaso. 8.. Chiba. K.. Sekamoto. H.. Arita. M. Potent immuno-
`
`Fl'Y720
`
`suppressants. 2-atkyi-2-aminopropene- 1.3-diois. J Med Chem
`1996. 39‘. 4451-9.
`
`1?. Chiba. K.. Hoshino. ‘i.. Suzuki. 0.. Masubuchi, Y.. Yamagawa.
`11.. Ohtsuki. M. Basal-ti. 3.. Fujita. 1'. W20. o novetimmunosup-
`pressant possessing unique mechanisms. 1. Protongation of skin
`aiiogrett survivat and synergistic oiieot in combination with oyoios-
`pon'no in rat. Transplant Proc 1995. 28: 1056-9.
`18. Kahan. B. D..Tejpal. H.. Stubbers. S.G.. Tu. Y.. Wang. M. Step-
`kowski. 8., Chou. TO. The synergistic interactions in intro and in
`wire of breouinar sodium with cyciosponne or rapamyoin stone and
`in ltipio combination. Transplantation 1993. 55: 894-900.
`19. Hoshino. Y.. Suzuki. 6.. Mesubuchi. M. Athena. Y.. Chiba. K.
`FTY720. a novei immunosupptessant possessing unique mecha-
`nisms. ti. Long-term graft surwvei induction in rat heterotoptb car-
`diac attograit and synergistic effect in combination with oyciospo-
`one A. Transplant Free 1995. 28: 1050-1.
`
`20. Kawaguchi. T.. Hoshino. Y.. Flahman. F. et al. FTYi'2tJ. a novel
`immunosuppressant possessing unique mechanisms. tti. Syner-
`gi'stioprotongatton oioanine tenet aiiogratt survivat in combination
`with oyciosponno A. Transplant Free 1995. 25: 1052-3.
`21. Suzuki. 3.. Enosawa. 5.. Kakeiuda. T.. Shinorniya. T.. Amarl.
`M. Moore. 3.. itoshino. Y.. Chiba. K. A novetimmunosuppressant.
`FTFYQO. havingan unique mechanism ofaotion induces tong-term
`graftaoooptance in rotand dog aiiotranspiantaiion. Tra ns plantatlon
`1995. 61: 200-5.
`22. Suzuki. 5.. Enosawa. 5.. Kaketuda. T.. Amamiya, H.. Host-lino.
`Y.. Chiba. K. Long-term gratt acceptance in atiograitod rats and
`dogs by treatment with a novoi immunosuppressant. FT1’73?»
`Transplant Proc 1995. 23: 13235-6.
`23. Dairies. H.S.. Collier, D.S.J.. Thiru. 3.. Decunins, M.. Calne.
`FLY. Long-tenn survivaiotkidney attogta its in dogs after withdmwai
`otimmunosuppression with ciciooporin and ezati'iioprino. Eur Surg
`F195 1989. 21: 85-75.
`
`24. Amemiya. H.. Suzuki. 5.. Niiya, S.. Watanebe, H.. KotakE. T-
`Synergistic effect otcyciosporine and mizoribine on survivai oi dog
`renai etiograits. Transplantation 1988. 43: 768-71.
`25. Masubuohi, Y.. Kewaguchi. T.. Ohlsuki. M. Suzuki. 0.. Amano.
`11.. Hoshino, Y.. Chiba. K. FTW20, a noiret immunosuppressant
`possessinguniouemechenisms. iv. Preventionotgraft mrsushost
`reactions in rats. Transplant Proc 1996. 28: 1054-5.
`26.Teshirna. K.. lrnayoshi. T.. Matsuura. M. Yamaguchi. 5.. Chiba.
`K.. Teresawa. M. FTY720. a nouei immunosupptessant. posses“
`sing unique mechanisms. iii. Phannacoiogioat activities in severe!
`autoimmuneand iniiammatoni modeis. 9th Int Cong lmmunol (JU'Y
`25-30. San Francisco) 19951111151512!
`2?. Chiba. K.. Teshima. K.. Fujil.A.. Masubuohl. Y.. Suzuki. C..Ada-
`chi. K.. Mishina. T.. Sasaki. 5.. Fujita. T. FTY720. anoveiimmuno-
`suppressant. possessing unique mechanisms.
`i. Rotationsttip
`between immunosuppressih'e eitects and seieotive decrease of
`penphornt mature Tcetis. 91h Int Cong Immunol {July 25-30. 33"
`Francisco) 1995. Abe15125.
`28. Arbones. M.L.. Om. 0.0.. Ley. K.. Flateoh. H.. Curry, C.M..
`Otter-i. G.. Capon. D.J. , Teodor. T. F. Lymphocyte homing andteuito-
`cyte rotting and migration are impaired in L-setectin deficient mice.
`trnrnunity1994. 1: 24160.
`29. Hamanrt. A. Andrew. D.F'.. Westrich. D..!.. Holzmann. EL.
`Butcher. E.C. Rois omg integrins in iymphocyie homing to mucosai‘
`tissue in vivo. J Immunol 1994. 152: 3282-93.
`
`at). lrnai. ‘it. Lasky. L.A.. Hosen. SD. Suiphation tequitementi‘or
`GinAM—t. an endotnetiai itgand torL-seieciin. Nature 1993, 361:
`555-1
`
`31. Berlin, 0.. Berg. E.L.. Briskln. M.J.. Andrew. D.P.. Kilshaw, P.J..
`Hoizmann. B.. Weissman. I.L.. Harrier-in. A, Butcher. EC. (Juli?
`integritt mediates tympttocyte binding to the mucosai vascuiar
`addressin MAdCAM— 1. Cell 1993. i4: 185-95.
`
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