Pharmacological characterization of RS 25259-197 a novel
`and selective 5;.. HT 3 receptor antagonist, in vivo
`'
`1R.M. Eglen, C.-H. Lee, W.L. Smith. L.G. Johnson, *R. Clark. R.L. Whiting &
`s.s. Hegde
`
`d ·.
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1011
`
`Exh. 101 1
`
`

`
`881
`
`Ollral
`
`RS-25259·197
`...... 1 a-.ical 11n1et11n1 {)f RS 25259-197 {(3a8)-2-{(S)-l-...
`biqdo[2.l.l)ocl·3·yiJ·l.3,3a,4,~,6-bcub~l-oa<o-I-IH·betiZ[4e]
`iloqu!DDiiAo bydtoehJoridll).
`
`.411tl-emellc stllllie8 in ftrrret.r and. dogs
`ne renu (Piotezyk •• Dl., 1982) 81ld the dos (Oylya et ,,.,.
`1979) are wdl established animal IDOdcb of eJDeSia lll'tlic:b
`xapcmd to c:aocer c:bemothmtpeutlc age~aca in a maDDer
`aimilar to that obaerwd in JIWl.
`Adult malo Corrcts (1-1.4 kg, MarabaU farms) wen: IIID-
`domly aasiped to ~t ~t gro"Upf. Eadl animal
`waa ~tizcll with mctoCaoc iDhalaot. A Jn&nlat vein was
`caunulated ad c:x.taioriud fl'om the ouUidc of the: IM:ICk.
`Followi.ug recovery from a.oaathala, each IIDimal \\'811 dOlled
`with citbcc RS ~197 (1-lOOJ&Ikg- 1, lv. w 0.3-IOON
`q-1, p.o.), Ol1daJJidron (30-IOOOJ.IIq-1, p.o.) or veblckt
`(lmlq- 1, tv. or f •o.) 30mlo pdor to adminlstratioa. of
`oilpladD (l01J18 q· , i.v.). Tho c:ompauads woro givco orally
`ill hard &datiD capmales. Badl attimal wu ooun~ fOr the
`IWl11ber of emetic episodes for S h
`following c:isplatiu
`administration.
`Adult malo dop (8- 20 q) (Haldtlton Research Producu)
`were taDdoJDiy a.igaed to clift'enot tntatmcut grCJDpS. EaclJ
`IIDimal W8.ll doled with either RS lS2$J.l!J'7 (0.3-JOOpg
`rca-•. l.v. or p.o.), vdJ.icle control (0.1 mJJcg-1, i.v. or p.o.),
`ondan<eeron (1-1000 J11 q-•, l.v. or p.o.) or balopcrldol
`(SIJI8q- 1, p.o.) at 30miD prior to the adminiatration of
`apomorpbino (O.Imskg-1, s.c.), or. 12~miD prior to tho
`admfniatntiou of either dacarba7Jno (30mgl:g-1, Lv.) or
`mechlorethamJno (OAmgq-1,
`i.v.) aad actinomycin D
`Stud/u on the li01I /lezollJ.JIII'Isclt r~ in rata
`(O.l$mgkg-1,lv.) or at 60min after the admbdstration of
`dspWio (3 ma kr', f.v.). Tbo oompounds were given iDtra-
`JnwvmolJIIly ~ S-HT or 2·mcth.Jl5-HT clidta an
`wcoudy via the c:cphaHe vdn or orally in bard gdatia cap-
`Immediate aad ~ vapJJy mediated zdb brady-
`sules. BecJl aDimaJ wu ClOUil1cd fOr the 1111111bcr of amct.1c
`canlla (rcfcrml to u the V011 lklmld-Jadsch rc:film) whida is
`~ for S h rolloviblg the adm~Dfitradon of elida emetic.
`spcdfk:aDy DJediated by 5-BT3 receptors aad. is aDlii&Oniud
`AD eDiotic episode 1ns deiiDcd u tho IUClaiSSful cvac:t111tion of
`by aclcctiw HlT, R!CqiiOr aGtago'lllsts (Po.zard. 1'14). RS
`Btmnlloh wntants, In aeparatc experimeniJ dc.signed to
`:ZSW-197 was ewl!lated for ita, ability to illllibit this ~
`ewniDII the duration of ~ IICtivity, doga were
`using oDdeDsctnm aud graniscUoa. u rd'cRnce COlllllOUIId&.
`pretRa~ with vehl:de (0.1 ml kg-1,
`l.v.), RS 252.SJ.I!J'7
`Male Sprap Dawley rats (Cbarlee RiYer, lS0-3110 g)
`(lOpg.kg-1, i.v.) oro~ {300N:Jra-1, i.v.) at 24, 12,
`v,:n, giWD food IUid Wllter Gd liblbutt, euzpt thoso use4 for
`B. 7, 6, 5, 4, 3, 2 or ill priot to the admblistration of
`lnttaduodeoal drug admlnJatratloo; these: rats were &prived
`cispladn, after 1t'bldl tach 8.lllmal was obsel"\"ed fm an addi-
`of food overuf&ht. RAts wuro aDIIC8thctized witb urUhaDo
`tional S b.
`(l.S g q•l, l.p.) and placed Oil 1D aquatic K. mocbale beatiDg
`pad to lnllinta!o. body te:mpenltun: at 3TC. Tho left j!JsuJu
`Haemodynamll: .1tudlu in anau~tlzed dogs
`'VCin or duodenum, crachc& and !aft Ccmoral vehl WCRI cao-
`lllllatcd Cor dtua admlnlatratioll ('LV. or l.d.). facilitation of
`MODIJ'd dop (4 male. 4 fcmalo, 11-16 q , Haalton Labor-
`atoziea) were anacsthetlzed with JIC'DtobadlitoM rodium
`reaplradon and lajeetion of Z.me.tbyl S-HT. rapectivdy.
`Heart nate waa derived from a limb kad n ECG monitoml
`(J61118ks-•. lv.). 1bc dogs- then ardllcWly VCAtilated
`with .Huvanl JCBpbators. A catlu:tcr .inserted into a llBRitld
`via subcfamal platinum oJcc;tro4cs ud wu RCOrdcd with
`artery was used for ~t or artcdD1 pressure IUid ror
`BCO/Blotada ampti1ier8 ~ to a Gould recorder (ItS
`);J800). A dose-response curve cq ~I ,.HT ($-100J18
`blood ~liDs (pH}b~ gas 4!1alyfh wid! 8. Conllllg
`kg-1, i.v.) Will t:OJIIItrllcted io each r:at to oataNish a subn.ax-
`Model 168 analyser). Tbc ipsilateml fmnotal vein was can-
`imal dOiSC (UIUIIDY 10 or 20 fi.J tg-•, i.Y.) which would elldt a
`11111ated for the admiDi.stratioo of test compound or vdlielc
`reptellJitciblo bradycanUc ~e&,l)ODSO. Each rat dlon receMd a
`and for tho admhddration of a maincmaqce infiJIIion or
`pcntobacbitDDe 10dlum (3-Smgtcg- • h-'). A MDJar 1P
`siusle dose ofRS 2525~197, ondansotron or grani.ctroJJ amd
`Mllcro-11p Catheter pmi:IOI'C transducer was ~ la.to the
`wu thco dlallcagcd with~ $-HT at S, 15, 30, 60, 1:»,
`left venlril:lo for the meumanent of ten ve11trfi:IIIN systolic
`180, 240, 300, 420 and 48011l1D post dodJ)g. A separate
`group of rats receiving ~ale (~~&fine for iv., dcionittd water
`pressure (LVP) and ldt ventdcular eud-diaatoUc pmsure
`(LVBDP). aod dpftll_. was obtai11cd by dcWonfo
`for i.d.) waa almlluly Coa1cd In acb study. PrdimiDary
`dill'crentlat1oa of the LVP ligual. The ript cxtcmal jugular
`uxpcrilnall showed that thoR WU DO evfdeiKo of tadly·
`vein Will iBotated and a 5F Swan-Gam: catheter (Specttamed
`phylula in the n~Spo!ISft to 2-methyl S.JIT. Duration of
`aodon of dto compcnmds wu UICNCd by clctcaniD!or the
`SPSlOSll) pl-=d In the pulmonary artGl)' to paml.t cletet-
`m.iDation of oantiac output (CO) by thennodllutlon 11Sinc a
`period af time for wbicb tho Inhibitory elfecll n:maloed
`Gould Cardiac IDJfox Computer (Modd 43S). Heart tate
`sigalficantly clft'cront fiom whicle conttols.
`(HR) was meuuted with a cardiotachometer tricgencl by tho
`In a separate scrlea of aperlmeuta, RS 2S259-197, 'l'l'hi:A
`R..wave of a Umb lead n BOG m:orded ftC~m ~k clect-
`applied topically oa the GbdomiDaJ ~ of mts. was
`owluted for its ablllty to bthiblt the rdlex. An aquecrna
`todes lnrerted llllbcut.ncously. Mean a.rterlal pm:sure {MAP)
`soludon of the dnJa 'WU &Morbed onto a Hill Top dwnber
`was c:ak:ulatcd u 1/3 (S)'Itolic arterial ~lie
`arteri.aJ preamre) + dlastollc ~ preulm. Dim:tly
`(lS mm bl cli~DU~ter) ill a volame of 0.4 ml. A fUbmuimaJ
`dose or .z.metbyl S-HT tbat could ellclt a reproducible
`Jll.Dnilored panmetm1 as well as dc:dronlcalty derived dpf
`bradyoudlD roapooac wu lint ~ m each rat. RS
`df.... and HR _., :n:conSod on a polygraph (Oould RS
`then applied
`3800).
`lSlS?-197 (0.01- 10001'8 per chamber) -
`PoDowlng completion of i11strwneDtation. each cfos wu
`topieiilly to the dtlpitltated abdominal llft!ll IUid the rat wu
`allOW!Id to equillbratll for 30-60 min be£91'1 bqpnn!ng a11
`cluii!Qlpd with 2-meth)'l S...HT at S, 15, 30, 60, llO, 180, l40
`apedme~~t Each dog rc:a:ivcd V\lhii;IG (1).02 ml q-1, lv.) or
`and 300 min post dose.
`
`Exh. 1011
`
`

`
`.·
`
`a liDA!e dose of RS 25259-197 (10, 100 and lOOOf'lq- 1,
`l.v.). Recorded panamete.a~ were measuml immMiatety prior
`to the flnt treatmCIIt do$0 aDd at 2, .S, 1.5, 30, 4' and 60 min
`atb:r each ~. .
`
`Slatittktll analysis
`Statistical analysis of th&l data waa performed by a rt>pWcd
`measure ma)ylis of Tllriauce (ANOV A) and, in some cases,
`Will foDowed by pairwise comparillona agaiast coa.trol at cadt
`limo period uting J.l"l$boTs LSD multiple comparison tt.oat.
`StaCiatlcal sigal&aJaco Will defined aa P<O.OS. Iu emetic
`stlldies, m m,. (dose required to produce SO% of dM: m.x-
`imal Inhibition) was caJculated wherever appropriate. ID,.,
`wu calculated 1l'ith NONJ..IN84 soJ\warc, a nonlinear
`modelliDa proeramme.
`
`methyl S.IIT iDduced bradycardia response, yieldiDJ IDJO
`e&timatea (9S% c:onfideacc lntcn>al) of 0.04(0.02~.06). 2.2
`(0.5-3,96) IIAd 0.J(0.01-0,J9)f'lkg"'1, m;pectively (Flgure
`2a}. Wben administac:d intradnodmmOy, R.S m59-197,
`ondaDsotron and ~n produa:d dosc-depcnclcnt in-
`hibition of the bradycatdic t'eSpOIISe (Fagure 2b), By the J.d.
`route, RS 25259·197 was much more ~tent (ID~ (9S% .
`oonfideooo interval)): [3.2(2.7-3.7J18l:g-) than oadansdcoo
`[144(53.2-234.2) pg q~'J and gnmisdtoo [49.1(21.2-76.9)
`1'8 kg'"']. Tho dnration of inbibitoey elfccta was dose>
`dependent for all tbroo compo\lllda (P"'1glll"o 3a- o). At cqul-
`drectivc dosea (lo'WQ!t dose required to prcdlXIO 100%
`Inhibition) die ctoratlon of lhe Inhibitory cl!'cc;ta for
`RS 2S2S9-197 (10 1'8 q-1, Ld., 420 mln) was peale!" than
`that of o.adansetron (lOOOp.gtg-•, ld., 300m:in) aud
`granisotron (300 I'C q-•, i.d., 300 lllin).
`Tramdermal administration of RS 2Sl59-l9'1 (0.01-1000
`N/duunber) produced a ~t IDhibltiou of the
`Malerlol8
`bmdycardla indut=l by 2-methyl S.HT (FiguJv 4a) yieldlng
`
`RS 25259-197, gnmisetron and lllldau.®u w~ ~ an ID,. (9S% ~ce intervaJ) of 32.8 (l2.8-S2.7}f'g per
`at tha fnstitute of Orpnic Clu:mfstry, synu.x ~ s.
`ohamber. lbc: Oilllct of !lie Inhibitory effects wu invenely
`proponioaal to the concentn.lioD of dM: drus in the Chamber
`HT, 2-moth'l 5-HT, actinomyda. D, ~ dacarbazlme,
`mecblorothalmillo aod apomorphizlo WCl'O obtDhled from
`(F18Ufe 4b). At doses of l-lOOpg per oballlbet, the
`inbibltory dects of the drug lamd for areater than 300 min.
`Sipna Chemlca1 Co (St I..ooais. MO, U.s.A.).
`
`Studlu on tlu: VOIJ lkzofd-Jarlsch reflex
`Wilen admloistcrccl illttaWDously, RS :2»~197 (0.01-lOpg
`Ira"'), ondansdfOD (1-300 111 kg-1) and granislotron (0.63-
`300f'Sq-') p~ dose-<fcpeudcnt iSihibition of tllo 2-
`
`120 8
`
`100
`
`10
`c::
`.2 eo
`~ 8 .1:.
`.,.
`.5 40
`
`20
`
`0
`
`~
`0.001
`
`b
`1:W
`
`100
`
`)
`
`10
`0.1
`Dose It'D lqf"1, i.v.l
`
`10110
`
`10
`c::
`0
`~ eo
`:;: s
`:4o
`
`~
`
`20
`
`'
`
`-20 0.1
`
`10
`Dose (J&G ~cg-1, 1.d.)
`11.-l Jllbibitory cti!XU ot RS ~51-197 (0), ondai1ICiroO <•>
`IUid p-anllctmD (A), ad:mlnlstanod ~...Jy (a) ....t iatft.
`dllodeaally (1>). Oil dla .2-medsyl S.HT-lnduccd bl:a~ Badl
`point lq)ldcDII the 111C11D :1: LO.-, II"" 8-10.
`
`100
`
`tODCI
`
`120.
`too
`c
`811
`0 :E 60
`:.:
`.5 40
`'#.
`.lO
`0
`-20
`
`0
`120 b
`100
`
`~ 80
`
`60
`.5 40
`'it 20
`0
`-U
`
`0
`t2Q. 0
`1C»
`c
`80
`0 I
`aa
`:.c 40
`.5
`~ 2Q
`0
`
`100
`
`.200
`
`300
`
`coo
`
`liOO
`
`too
`
`200
`
`300
`
`400
`
`600
`
`100
`
`400
`
`500
`
`300
`200
`1ime (min)
`.._ 3 Dnnllloa or the lnhlbitory dl"lldll or RS m.s9-197 (a),
`~ (b) a1111 ~ (e) 011. lhe .2-melhJ(·S.HT·iodul:ai
`~~~(a) RS %.5259-197, <•> Sflsks"1
`, Ld., (•} tONka"',
`Ld.,(A) 3011Ctg-1, Lei., (b)~ <•> 300fl&k&"1, i.cl., (A)
`tOOOpekr'.- Lei.., (o) 3000.._"-:- 1, :..t. (c) Orlll>lsotrcm, (e)
`tOO"'IIr', 1.4.. (A} 3001'sta- •. Ld., (o) IOOOJ1alrg"1, Ld. ad~
`point rq>~ lhc ~UC&D±Le.mcaa, .... a-Jo.
`
`Exh. 1011
`
`

`
`Antl-m-tetic activity In feTTeu and dogs
`Compued ...ith whiclo control, IlS 2SlS9-197 (1-30f'8kg-1,
`iv. and. l-301'1.1c&~1, p.o,), olldansoUoa (30-IOOOpgq-J,
`p.o.) IUld ~· (3-300pgkg- 1, p .o.) liven 30min
`prior eo dsplatla prod1ICOII llipJiiamt 8lld cta-dcpcudcat
`mluctioa in tho I1Uftlbcr or emctiG cpiaodca in fctn~ts (FI&uro
`S, Table 1). When adndnlllered orally, R8 25259-197 wu 2
`IUld 13 fold JDOR poamt than p1ll1laetroo aud oudamctroa.
`respocti'WOiy.
`AI shown iD F'JgDtO & 8IICl Table 2. RS 25259-197
`(0.3-IOOpgt,-1, i.v. aDd 1-100jAgq-1, p.o.) aud ondan-
`
`•
`
`•
`
`•
`
`10
`0,1
`AS 25%59-197 (Jlg{chamber)
`•
`•
`•
`
`•
`
`1000
`
`120 •
`
`100
`c 80
`.2
`:I'! 110
`P-z:.
`,5 40
`~
`
`:10
`
`0
`-20
`0.001
`
`1i:ZO ll:f
`
`\CO
`
`c .,
`~ till
`~
`411
`'i/.
`
`:.10
`
`0
`
`-204-~~~--~~--,-~r--r--,
`-110
`tiD
`0
`10D
`1SO 200 250 3DD 350
`Tlme(mln)
`fl&an 4 11121ibi1orJ cffecU or RS lm9-19'7 (admlai.lt.cral lfBIIIdop.
`mally) ODIIIo ~ S.HT~ ~ {a)Dow-ic:spuwll
`· · cune to llS ~1!17. (b) Duradoa of' the: inhl'bltoly ctrcc:t. ot ItS
`I )~59-1'», (•) IJII per clmmbcr1 (e) lOPe per cbmber, (A)
`:t a..c.meao.
`1001'1 pol" dllallblr. &da point ~ tho -
`n-10, -slpll~ ciUI"enDt (P<om> from 'lddc:lo cootml.
`
`•
`•
`3
`30
`10
`RS 25268-187 (Hq-•. Lv.)
`"*'"" s Jahibltmy cm- or la~rBWDoilll)' admilllalllll"od RS 25259·
`
`V.lt
`
`1
`
`100
`30
`10
`Ondenntfeft CSIQ kg-•. l.v.)
`lablbltory ell"el:ta of iDtraveaoully ~ RS 2m9-
`llpre 6
`197 (a) ud ondalllctrOD (b) on dsplalhMudDCOd omWI Ill dop.
`197 aa ~ CIIIICdl Ia temta. J!lldl eo!Uma ~
`tbe IIICPI f a.c.mean. n .. 6. *Sigalflcandy lllftl:l-cat (P<O.OS) !1om
`Eadl po!Dl ~ tbo llleall :1: u..ntle8D, tr • 6. •Sfanlflcanlly
`4illmaa (P<o.05) r-. ~ cootrol (Veh).
`....blck GllllbOl (Vclt).
`
`KirOn (3-300~&&kg-1, i.v. and 10- 100fllkg'"'1, p.o.) pro-
`dulzd do~t iuhibidou of the cmesic illd\ICled by
`cisplatin, mlnomycio D, dal;ubamlc aDd mecll1orcthamiu
`in clop, ID.,. cadmates arc abowD in Tahlc ), When
`adminilterocl orally, RS 25259-197 wu about 30 fold tnore
`pomnt than cmdauaetton 111 an IIJlti.anc1ic against each of
`tho omctopDio apat3, In studie. dcsipecl to CIUIIIIne tho
`dutation of &Dti-eadc aotmty, RS ~9-197 (30.wtg-1,
`i.v.) waa dl'ective for 7h in lnhlbitlq ~
`emaall, ~ tba anti-emetic adiYity ol oudansctrosl
`(300 I'& Q-1• i.v.) last.ed for 4"h (Figure 7).
`Neither RS 2S2S9-J97 (1-1000 Jl8:ts-•, p,o,) oor oudan·
`aeuoa . (1000 Jlskar'. p.o.) 111m11 c:!fccti..., In iDhlbbing
`apomorphiDe lnctu-t eme.is ill ctoss (data aot shown). ID
`contrast, haloperidol (Smgtg-1, p.o.) produced cigDificaot
`hahibitlon of apomorphine indlk:ed emeaa (data not shown).
`Haemodynamlc effec.ts in aN~esthetlzed tlog.r
`Baseline valuea for the measured pammcters did not cWrer
`figniflcalldy betwoan tlu'l vebh:le and RS 2S2S9·197 treatment
`groupL A.dminiatration of vehide or ItS 25259-197 luul no
`alplllcant dfccta on MAP, 00, dP/tl'I' aud SVR. (data not
`
`'Ntle 1 m. ostimatof or as 2~·197, ~ IUid
`graDiseuon aplnd dspladn-lnduad lllllaill ia feJm~J
`IJ),., 011 q-1 (9$% c:o~tfideaCII lat.rva!J))
`b.
`p.o.
`3.2(1.6-4.8)
`1.1 (1.0...1.2)
`ND
`43 (IS.0-100)
`. 6.9 (1.0-40)
`ND
`
`ND • DOt· dotcras!aocl.
`
`")
`
`.I 1s
`.f .. 12
`·t
`~ J E " z
`,.
`:
`""8 11
`i 12
`l> i 9
`0 .. .. •
`i 3
`
`.2
`
`0
`
`Vet!
`
`0.3
`
`s
`
`300
`
`Exh. 1011
`
`

`
`shown). RS 25259-197 produced a algnlificant decn:ase in HR
`at IOOOP«la-1, Lv. but only at 4S min post.drug (Figure 8).
`
`Studies on 1M Yon Bezold-Jarisch reflex
`InhibitioD of 'tho 2-mcthyl S.HT iDduc:ccl brad)=.rdia (Von
`Bezold-Jariscb ~) Is a usefo1 test ~ tho IIV8luuioo of
`S.HT, ra:epto:r aotqouiats In rivo. In this asaay, KS 2S2S9-
`DflleusiJoa
`19'7 administered oither lntra•c:uousty, intradUodeaally or
`~> _, cll'ectl~ ill IDbl.bltlos the ~ to
`The dlita obCaiDN in tho presciU study show that RS 252»-
`2-mtllhyl S.HT. By the ia~u :routo, RS lSlS9-197 was
`1971 a novel 5-HT, RCOptor antagollbt, displays ~
`approximately 3 and SS fold ma.re potent than gi'IJ!iseuon
`phamlacodynamlc and pbarmaco.tinetill difl'cm:acea from the
`and ondaliSdrOn, rapecdvely. Tho alinity of RS 2S259-197
`S·IIT1 m:eptor antagonist~, oudametron 4Dd graolseUOD.
`
`DtiiB
`Vehldto {mlkt-•. p.o.)
`'RS :zm!l-197
`(laat,-•, p.o.)
`
`ODdaluiCraa
`{JlJI ta-•. p.o.)
`
`o-
`0.1
`1
`3.2
`10
`31.6
`100
`10
`31.6
`100
`316
`I GOG
`
`DriCtllflcflle
`(30 IDS q-1, l.v.)
`14.2± J.6
`NT
`12.1%2.7
`6.&:t:0.2"
`cut~
`oto•
`N1'
`Ia.&± 1.1
`6.2:1: 2.2"'
`3.0 :l: 1.2"
`o .. Ho.1'l
`
`Nlllllha Q/ -tic ~
`A~ D
`M«lloul/rllllrllte
`(0.15matr1• Lv.)
`(OAIIl&kr', l.v.)
`9.S±2.9
`14..5±2.3
`NT
`NT
`4.5± 1.4
`5.8±0..6'"
`6.7± 1.6•
`2.8%1.94
`1.0± 0..,.
`o.3 ±'o.3•
`3.3 ± 1.9"
`0±0"
`NT
`1.7%1.0
`8.S± 1.3
`2.8± 1.5"
`o±o•
`
`NT
`ll.B ;t 3.1
`JO.U:1.9
`4.2±0.&•
`1.5 ±0.6•
`
`Cllp/tllflt
`(3maka"'1, LV.)
`14.2±3.3
`12.8 ± 1.9
`16.2 :t: 2.l
`4.0:i:U"
`2.7 ±0 . .,.
`0±~
`12.7± 1.2
`t8.3±:J.4
`IO.S:t: 1.3
`3.H:O~
`2.0±0.9"
`
`....,..3 IDa (Iraq-') esdmat.cs o1 RS 252.S9-l97 ud onda:asetron aplmt varloaoa t:llldDpUa apt& l:n clop
`
`~
`
`RS~I'J7
`
`Oudaudroll
`
`R#utll <1/"
`lldtttflrilftQtUm
`
`Lv.
`p.o.
`
`Lv.
`p.o.
`
`Cllp/4llrl
`1.9
`(0.28-t;J,O)
`8.!1
`(3.6-20)
`46.0
`. (17.0-74.0)
`160.0
`(41»-%70)
`
`•
`2
`
`0o
`
`12
`8
`•
`Dose time lhl before ciaplatln
`Jfpre 1 Dutado11 of tha inllibitory Glfco:D of Yebkle (O.IIDIQ-1
`)
`<•>. RS 2ll59-197 (30~;oed<•J ~ olldo.IIJIOI!'Oil
`(300f1sks-1, t.v.) (0) ou
`email ill clop. Dop
`w= pt'O'CRa~ Wilh lbD dnlp at Z4, ll, I, 7, 6, ~ 4, ~ :111114 I II
`prior to die ~ ot dsplada. Bad> point I'CpRSCilta tbo
`-
`:1: ,.._--. "-6 •Sipificantl7 dll'e~a~t (I'<O.OS) hul vdll-
`do c:oalrol.
`
`Elnetttpnk ~·
`~IN .4t:t1Mmfd,. f)
`4.9
`(0.45-54)
`l.SS
`
`4.1
`(2.1~.1)
`9.1
`(7.3-12.0)
`80.0'
`83.0'
`
`200.0
`{47.0-900)
`uo.O'
`
`~.~~~
`
`4.4
`(l.J-9.1)
`3.0
`(0.8$-10.0)
`36.0'
`280.0'
`
`200
`
`\ 176
`e
`..
`!I
`! 150
`~
`t: • • 126
`
`%
`
`t1
`~
`
`•
`
`1011
`-10
`
`0
`
`10
`
`co . 50
`%0
`30
`limeCmiPI
`J1pno a l!ll'oc:aa of lntrav-l)' admlnialai'Od RS 2S259-197 Oil
`l!cart m:o ~ In anactthctlud dop. (0) Valdale, (.) R8 ms9-
`19'7 (lOJA&ta- , lv.), (~) R.S 2m9-l!n (IOjlgq- 1, Lv.), (0) RS
`~197 (lOOOf'&.,-1, i.v.). 1!acb FOiat reprcaca.ta tho mean±
`a.c~ n-6.. ~tty dilflftllt (P<0.05) from 'ldllde coa-
`nL
`·
`
`6()
`
`70
`
`Exh. 1011
`
`

`
`R.M. Y!en st B1
`RS 25259-117 a pot!!!! 5-1111 lllf§onkt In riiiO
`for displaciJJa ['H}qulpazine In the rat cerebral eortc11s lOA
`Jlaidea c:Gplatln. other eaoc:er chemotherapeutic agenbl
`nda u dacarllazine. mechlorethuame amd ac:tinomycln D
`(Woos er al., 1994) lllbereas the reported p14 wlUCII for
`onctaoaetron aDd ~~~ In rat tissues
`l1lll&ll frooa
`also rQ8C emesis althoup of a ~ severity. 11leso agmta
`also inducocl ==• tn dop which was dosc-depc:udentty
`8.3-9.0 (for ood~D) and from 9.2-9.8 (for graniaetron)
`(Kilpatdck •' Ill., 1990). 'lbua the order of potclley iD
`ln.bibltcd by RS 2SlS9-197 Indicating that the auti-ametlc
`illbibiti:ng the Von Be:zold-Jarisch rellcx parallels the relative
`eilecta of this compcnmd are DOt restricted to cisplatlu aloec.
`aflinldea of the tbnla compollllds at S.HT3 11Xleptors. By the
`In tbe eae of clacarbuine and llledllomtbamiao, C01119letll
`lnh!bltion of the -tiQ epimdea wu ach!eYed wltb
`iatradulodcDal route, RB l52S9-l97wu about IS ud 4S fold
`JGOpgt:c-1• p.o. of RS 25259--197. Ondan.setroa wu also
`moro potalt thaD onclanaatron and granisetron. The i.d./l.v.
`poteocy ratio for RS ~197, ondaosetron and gnmisetteJS
`cft"ecdve agaiDit tbc abovo ~ apts althmlgh lt was
`was ealculated to be 80, 6S al1d 490. l'IIIJPtiCli.vely. These data
`about 100 folclle&a poteDt than RS 2Sl59-197. Abo, at the
`IUgpt that RS 252S9-197 aDd OJJdansctmD pouess belter
`~ tadcll, ondaDIGtroo could prodUce c;oJnpkte bloclca.dc
`of tbe emetic episodl::s oDly apinat 111ecblordhamioe b1ll n.ot
`bloavailabDlty oharaoterbt1cs than gruiiOtron. Co1J51!lluently.
`by tho iatraduocltllal route. the ~ bioavaUability and
`apimt cisplatiu. daca.tbazinc and actiDOIDyda D. RS 252S9-
`hlgbc:t aftlnity of RS 25259-197 for 5-BT, nx:optora IIIID it
`197 wu Jndl'cctive against apomorpbine-llldut.ed emesis IDI"
`gcatiua that tho Allrl~ dfccts are DOt a teNlt or
`the mOBt poteo.t of tho ~ ~pounds. Bosides being :mon~
`potc:ot, RS 2$259·197 abo appeus to have a longor dunuion
`dqwpiae o:a:ptor antaaooiam.. Such an ~on iJ
`CGD81atcnt with Upnd binding stucliea wldch ba~ daoWil that
`of ac:tioD; IU IDhibltory cffocbl pcniltcd lonpt than thoeo of
`pullll:b'oo aDd OlldaJJBetron wbao all were tested at equi-
`llS 252S9-197 docs not interact with D 1 aud ~ n:ceptora
`offectiw doRs.
`(Woa& 11 aL, 199S).
`oral adminbttatloa of clrup to caneer paU..tl Ulldergoing
`~thml:py is problmnatic owinf. to the hi&h illcideoce of
`Haemodynamic strulies
`cmesJs .iD thelo patients. Tb11:1, awilability of a S..HT, recep.
`tor aniBzoojat In thc fon:n oC a tramdmnal formulation
`~effects ofRS 25159-197 OD bacmodynamial in clop W1:t0
`studied to detctmfnc whether the compoUDd cvob:d c.ar-
`would greatly facililate the manacement of ~ in ~
`I pat!cllts. The preownt study 11M $hoWD tllat RS 2S2S9-t97,
`cliovucullar effects at dm• that showed anti-emotic activity.
`when admjnia~ by the tranadcrmal route. causes pc;tent
`Thia study was Ullda:takca in view of the reported dlnical
`iDhibl.tion of tbe l·methyl-S.IIT .mduc:ed
`and ll'llStaiDed
`cardiovascular adverso effects reported with olldansz,ttoll
`bradyc:ardfa. 1besc data wssest that lnulsdenual formula-
`(Ba1l:ud lit a!., 1992). RS 25259--197 produced a modeat but
`tions of RS 2S2S9-197 1aay pro.o to be convenient druc-
`sfpifiamt de:a'CIIIIe in HR at lll00f&8 q-1. H~. ID
`dop, amJ..cmctlc df'octs or R.S 25259-19'7 were: obscrvc:d at
`do!Mry systems In patient~ axpericiiCini emesis due to cam::cr
`doses u low 118 1 flgltg-1• Thus, RS ZSlS9·197 wu eaen·
`chemotherapy.
`tially dl:void of any acMr&e canUovascular aido-e&cta at
`dose8 tbat produced antl-ernetic effects.
`Anti-entetic studiu
`In INDIDI8l}', RS 25259-197 appears to ba a novel, orally
`actm S.HT, ta:eptor &lltagoubt that ia mmc potent and hu
`The ~ dlUis of antkal1ocr drop is most pro-
`DOunccd 1rith p!atimlm drop sucb 1111 claplatia. Cisplatin,
`looser duration ol uticll tlwl either onclust;t:ron or
`a
`whm administered to clop and remu, ptoduces an emetic
`granismon. A. ~ssed in tho IntrodliCllon. cwnrntly
`ancl bc:havioural proflla wlllch most clotdy R8CIIlbks the.
`available 5-HT, re<leptor antagotdsta I1ICh 1111 ondallll:tron
`ll1lfti:r from drawbacks moat DOtablo of wbich b thoi.r poor
`clhlical sympto~m (Gylys d r~l., 1979; Florczylt et al., 1982}.
`oJfcdiveaca ID cootrolliDIJ mild and delayed cmctit. It is
`The pruent study has shown that. RS 2525~197, admini-
`undear Wllctbcr tbia is dno to the intriullc pl'operty or the8o
`stered intravenously or orally, pofaltly illh:ibits QlplatiD
`Induced IIIDISia in both tbc fcm:t aDd dog. Comparison or the
`drugs or Is a COJiliOOIWity Cor an 5-BTs n:ccptor autasouis11.
`Tho prese~~t study baa shown that. at least in auimal modds,
`oral and-c:medo potmcy In tho ferret showed that RS 25259-
`ItS 2S259·197 n:pRSeDts a slpificant improvement o'm"
`197 was approximately 2 and 13 fold l11011' potent thaD
`oodanact:ron as a11 ami-emetic qeat with us)leCt to potenCI)'
`~aDd ondallatron. zupcctivdy. In the dog, RB
`and duratlcm of acdon. It should be noted that ~ll
`25259-197 was about 30 fold more poteot thaD ondauarou
`bill also boea reponed to possess the 8111118 advaotaps 01W
`.
`in iDblblliDJ c:!splatiu.Gduced c:mz:sls. The lowor poteacy of
`orulametron (Andrews e1 al., 1992). A. the pn:scnt study
`:-· 'l ondalllct.totl ralalivc to BS 252,_197 iugaill ~t with
`tho relative aft!Dlty of tbae eompoUDda ror s.HT, ~tors.
`lacks ~0 u.ckmetic eftkacy data with gnmixttoa, it ia
`..
`1Uidear 118 to how BS 252S9-197 would compare with grlllli-
`When laCed at equi-dfeclive dOICf in clop. RS 2SlS9-197
`setfOil. Puturo sQJdic& should. thord'orct. bo aimod at a direct
`appeaml to ~ve a lonFr daration of antl-cmetio adion
`comparison of the two clnJp. Studies aro IIlio in prOSJMS to
`(1 h) than cmdamc:tron (4 h).
`evalllllte the c!lllica1 ~ ot RS 152S9-197.
`RB 2SlS9-l97 procluocd COIJII)Ietll inhibition of emesis
`ll1clllced by dspla1iD lo tenets (l.v. but not p.o. rvuto) and
`dogs (p,o. but not l.v. route). This i& a pertinent ~~
`became, In thcl dinlcal setting, it ill mtical to ~oduce com-
`plete block rather than patdal attcmlation in the llDDlbor of
`CDietlc cpilodes, 118 avea mi1d IliUM aad emeala c:an ~
`coDl))tolllbe the succcu or chemotherapy. Tbc maximal
`inhlblrory eft'eclta of RS 25259-197 appear to depcmd on the
`route of admhdstradoll. Tb.c pm::isc rcuoo Cor this paradolt-
`ic:al futdlng Is uudw- at pc-c:sent.
`Ref.-
`AND!U!WS, P.L.ll., .aANDARJ, P~ DAllVEY, P.T., IIINOI£\M, S.,
`MARa, 8.11. & BLOWER, P.R. (1992). 1\no all S.HT, tea!plor
`utasoalsls tht> ll&l1lil Ew, J. c-, 28A (SUppl 1), s;z.-$6.
`JIALLAJlD, H.&, IIOTilNO, 0. & BOnlNO, I . (1992). Ondamdroo
`..... dim pam. r-t, 3411, 1107.
`OOSTAU, B. A NAYLOR. JU. (lm). Neu..o~ of ama!a
`lD robltloo to c:Wok:al respaa801. liT. J. c-o-, 1li' (Suppl).
`512-SU ..
`
`FnZPATIUCit, I..R., LAMDBilT, JLM., PBND~, C.li., M.U.llN.
`O.B., BOSlWICK. J'.S., OESSNI!lt, O.W., All\BY, J.B.. YQW-
`SIII'YliH, R.D., FBNDBL'lUN, ll.O. A DI!CJJOR, D.l.. (1990). ltG
`12!11 S: a poteat s.•ydroxytryplllrnhle-3 aalqoala tbac If aa
`orally dfccllye IAblbiiOr or cytDtoxlo dnlc..mduoe4 emcds In tbc
`fend aacl dog. J. ~cal. IJ». 7Ttet-•• 254, 4S0-4S5.
`
`Exh. 1011
`
`

`
`. ...
`
`168
`
`(~July 21, 1994
`Rnlltd Oetob« 11, 1994
`Aa;qwl Oeto6er 18, 1994)
`
`Exh. 1011