AU2013211529A1 - Compositions for treating or preventing obesity and insulin resistance disorders - Google Patents

Compositions for treating or preventing obesity and insulin resistance disorders Download PDF

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AU2013211529A1
AU2013211529A1 AU2013211529A AU2013211529A AU2013211529A1 AU 2013211529 A1 AU2013211529 A1 AU 2013211529A1 AU 2013211529 A AU2013211529 A AU 2013211529A AU 2013211529 A AU2013211529 A AU 2013211529A AU 2013211529 A1 AU2013211529 A1 AU 2013211529A1
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compound
attendant
methods
agent
ampk
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AU2013211529A
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Maria Alexander-Bridge
David A. Sinclair
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Harvard College
General Hospital Corp
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Harvard College
General Hospital Corp
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Abstract

Abstract Provided herein are methods and compositions for modulating the activity or level or a sirtuin, thereby treating or preventing obesity or an insulin resistance disorder, such as diabetes in a subject. Exemplary methods comprise contacting a cell with a sirtuin activating compound or an inhibitory compound to thereby increase or decrease fat accumulation, respectively.

Description

COMPOSITIONS FOR TREATING OR PREVENTING OBESITY AND INSULIN RESISTANCE DISORDERS Government Support This invention was made with government support under Grant numbers GM068072 and 5RO1-AG19892 awarded by the National Institutes of Health. The government has certain rights in this invention. Related Applications The present application is a divisional application of Australian Application No. 2006266125, which is incorporated in its entirety herein by reference. This application is a continuation-in-part application of U.S. Application No. 11/174,000, filed on July 1, 2005, which is a continuation-in-part application of U.S. Application No. 11/027,779, filed on December 29, 2004, which claims the benefit of U.S. Provisional Application No. 60/533.712, filed on December 29, 2003, and U.S. Provisional Application No. 60/588,643, filed on July 16, 2004; all of which are specifically incorporated by reference herein. Background Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. Obesity is a chronic condition that is characterized by a body mass index (B MI) over 25. Both congenital and environmental factors, such as exercise and eating habits, contribute to the disease. For instance, the hormone leptin has been shown to be involved in fat accumulation and regulating eating behavior. Several animal models of obesity result from mutations in the leptin and/or leptin receptor gene. In addition to affecting the lifestyle of an individual, obesity can lead to a number of complications and diseases, including insulin resistance, Type II diabetes, gallbladder disease, hypertension, cardiovascular disease, hyperlipidemia, sleep apnea, coronary artery disease, knee osteoarthritis, gout, infertility, breast cancer, endometrial cancer, colon cancer and lower back pain. Diabetes is a disease that shows an acute symptom due to a remarkably high blood sugar or ketoacidosis, or as well as chronic, general metabolic abnormalities arising from a prolonged high blood sugar status or a decrease in glucose tolerance. Both congenital and environmental 1 factors, such as exercise and eating habits, contribute to the disease. The pathogenic causes of diabetes are insulin productive disorders, secretion disorders or reductions in activities and sensitivities of the secreted insulin. Diabetes is largely grouped 1 q io the fo tri two typeat ddets meifus (HArkin as Tpe diad) and nod uiieedn dibotos (1}Jn)A(alsO kinWan Ty'NV' dibk fr Obty a gn y dineke4d to suppreksing dhe appatt of th aubjerg. Wherreas a giere of appete ap rssants are available(Iihypion tnae athsado, oista phendimeerazine. pttentin ibutxaeinxe)the~se coman.and may not be eftativc n at aubecis ornnay heo Ithntued ent&. Accordingig new tmahnients S obiY an needed j\ rm:nbar ftett nents for diabetes ant well kono. and inchado' osal hypogiyremia ag*:uha dtyua etMms .Nli setdni mn t ilhatsride cbitorpocpamide and gibenamiide >igvaaidea' (for exmplemorfifrr ande baa ) that haerezasedacose apptake and ditros m andg ucridase inibiors for enxsrple, acarbose and vogibhose):. .ddhion thinaaidindn such as tngitazone, niiaatne and pit aonw, we WSd to sam4at nslneSistuw rd d anaae is ercty mtaiankd wnth a weight gain. Tian there isathill a need for more efi avefiarapaes for diabetes. -v-: a 1( d ." Curredy i8% and "a% f adittin the Uited Sates rdiabxtik r oheseg reSpctivey With hexanaherf inmdyides Offened wVh dnhabte tiaatl wi tVp, 1 diabetes. and obesity on thnresse. thereis ade need lor medications that prevent sad treat these oar Shunary Eranded herein are mhods for treadiag or preveating obesity aedicr isuudn resisance disorder. auch as daiaea. vepale a~s hypensulininia sand insulis ntteas a sidrt In rne eashodimna.the method corpse aansisatia to a subecin ned hudf threatiall efectveamount of ass agnt that increases 'b :5edeliQyardier psosteeld ofe rgtstn such as SIRfTI or2C The agent tay be a smtawi atigasting; c 'zampod, o a alt or prodrug the ot int aria va ng cdpond prsfobij aianuihear huunmn SirS,2t, & J NI, protein activity. 'Te aitncin div ng compound preferably is a compound whah bass msrma selected ion' th goup consungp of fonaulas147Q 5847. 91 or A or a a sr prodng the<"c Simai ativaating osmperda ass be (laura tteset salrnI hvnnavewnest essshNg cialdenneat tarsri na sad anthbocyansibs or analoga or earvatives utheoh ins certan may c Rtonkz2 lmcomipound doea nc4 have nvgen- f mesa of ahmtrredae aht acttingcomprmdealsoinorte oen etij eder pnttet~ kvetn 5oMf'uate protein kina e (AM4PX4 c ertain mbdunshemhdfrhe ompmser admni sedg tte sajget a therapetiafvethtive atueit of a eond agent tat(i) increases bai nn and/ patein level tAMt vated proti kinae (AMG ionrease the activity annior protein level of a sirtain; Oti) is ar atadibed agni (iia am bst gn AItso provided erein areamiotnd for promt<ng Weight ga a subect e:g fod tretin eAchexia o imima dmintiedag to a satct ened h ha cetve amoat of atn agent tat deoresses theaeatvity and/or protein teveot 01 sCun suc S 111R Tor Str% Pretmoy~ the naditanihitory rompound t a compnund selected fiom the ign fp d represented hytres 4%$45 53 and 8%9O, or a salt or parodnmaj thereof lhkrred sirdi n ittittanry c m pnds alo deense or 0bit the ati end/or rte ivei of $ t AMElartadtng protein kitaaso MPr* t certain mbdiments.the method further compises adminiteings the subject a Cempe acay (ffective an Of a 01tnd th'.iay 4 met ede o proen 0el of a irin~ (i) decrases the activity andar protein level of$AMP activated proein kiase 4",..prSoou eghkai An'o provided is the itse of ' ' si "naevtn copu~oe i ojnto wih at eVoN get, fo the inanufaOctme f at mediNament for treating cir preventing an insatn matiance disorder and teue of a sirtun inhibitory comtdn alone or in conjunctiont with a second agent for the mnufotacture of a mnedicarent for promoting weight a in at~ el Trief Descrlption of dhe Dlrawings i/igure I shows te stinaladen of SIPAT catrityi rate by 100 fA4plant paphandis (Tabl I iguire2 o the eafeit of 00 0Mibenes andchakoes on SRT catalytic rae (Suplemeagy able I) Itignre 3 shows dt et of I 0 it flaones on 541iT 1 caalytic ado (.Supplemreiihr\ Table 2> N gore 4 alaw th effect4 of i 00 M flirvnes on SiRTi' eI ctlytc rate (Seppiementaty Tablec 3> gurtshwsthe Veffett 100j iownes, ik vane4e a aboneanidina on S NlT :aalyt of 1Star T0 6 Figuat 7 shows te affect of tUV gM catfe- s (Fvlm nTa a Qty S0 i Fi vt? hwhe Anffn of 10O M free r dieAd rotuCeva (pd l SIRT eatalytic ras' (Supp ncry Table 6 Fiie( shtowsa thie e 0 o 0,0 p mkIe.olkT us munde'en SI le Is rate (Supemenay Tabk N 1ir 1 $' show.h diec of 100 M of vi-aro3matra on SI~i cUayve m.i (Supplekmer Table 9) K 10) awa the effect o' 100 sM orflew taxntn andO SIR 1 d yni pt a,9) Fignti how $te Nmo o4f ' gMo e avmn analgen IRT oEtalietavte (ahk 10) e s N fNt of 100 ( M <C w tsvtatwl Z, a s T erinvydi rate tIdd Ngm 3.4w me effea of 10 (gM nO .avratte*Iandagr aN IRT f catalyicte (Tab.rv 4) esalem -an (Tabe 13 1 ( Figre 16 shos5 synthetic ingats~ t f atid odao g synt$'i.gle' 15) Pigte 17 hoS aynthetic I termedliater of tevtr1 do an Nite$S~< isthe Niger f~ S1 shocythetit nvermediates of esaeratroi kndag. syntt*eSi(a UP')1 Figure 9awRS wynthetic intemedite of tesveratlekeao hyrahi (Ta V 194. Eiue 2O- hw sttatitrs4 n thid aceto ofljj abe >) Figre 21 showsitunniir anOAKfl nhbto of SIRM (Tabs 21), Figtar2 22 A 5howttO rvatl se4um ucos lirn 22B shos that rsvoarfira inwersna aos in Tat and T states, fiene 22Cshow, that naesraIMnaS ia insulh"Uisediv itn Defantionts attt As used ,W n OWSm n s andll Oa shax! uav the wningay set h erdv 4 tNhiss doti ed othercizeN alttechnied~y~ andaieman term ats here have the nie meanin as ca y C:ndtood tO 0oof ordinary skill inthe art. The>tirtgular .funs hkt anhn oathO" indlade thtal reteono ueses Lth contt ceydirtates othetwseO The tsrxn %et in used hesein to denote a chmi dcal compound, a ixturof ehemki it mp lK'd a bnsetd ical m oloeule (uch as a mwluc vtid an andbodxy a protein #rpron teot a porpmd)m an eXflAt made tha m mateaL such as bacteria. pa n. a 4g or anhna (parraicolrty ornaliafr) ellts or tissues 'The activity ch agen ts masy meM e su she Ms a rapeutc agent tah i a biolgian pysiongelly orpbarnaringinalg active s~atane r substsnees that antselocady or systenricdlv in a cpee 4 $tneti~ ne Vat 'ivks to remasnt at nst one activity ofa ailttain. pnteij gekhraby by at G5st shout 1tW 51%101% A r more. "Advdhg c slaf oproitehf rel to the aon orirodoutg activated tirada poat ei a siton protein ha at is Ctparhk of pehnnay toast One of uts ioagh l atmivitex wnh n increase1t Yft att least shout K0% .SN 2 fid or nioe. Biogcat activides of aitnk'proteins itinde At de v'tAgk of h tonns and P53; extendiog ifsaan iacratig ge aabi ity; ...... , n jxt, sio ng Ora AS rid n conllng Mlygeaa e adzdpes ewe mothe*arr "an ghter-ees An "acdvating comporsd "irtncdvarttg omrpourd" or a 4 rinn activator" t rets to a conmpound that activaes a cirtuin pant nor strraulates or misses at Itact <e andoyf a 'iti proten, in certai embodimenrt aiactivag compoun'md may hna fanncrtade"ted Pontega a.femua 'k2"4 '1an ' The term agmnf is used herein to denote a chemical camp a mixture of he componds, a brdo~gical .macmoleuie(soch a a uclic acid an andyda proten or partiron theeot; e g a pep tide or an extract m'ta %sm bioiogicat matedas suhas bacteri. planta. tng oeii (atichd umslian) cols or 'tist'$ The ai ofsach aatls may inderit nuable as a "hampootic agon( s biologkdly. physioogicay or phaaoogicatly 'active subsanna (or substanccs)ha cts locany or svenalay na subject "S ritanf inhibition* refers to dereasing~ at aton igyof a sirtuinpot n p rraby at atst abondt%,0% 1. mo mr 'inibiting oomp md" oriuin inhiby comPound reer to a conpou 1 n h n a s ndy of a tuo pre iiIn certain inbodinients, a sirmin ,nhviitorv compot may hae a fbnada locted fronr the group consisting a? L antias 19", 4.1,53 and 88"0 A. ~fn that ina rtundl l ci twon .referring to a cumpod means a compoud hat is la a Itum, o. a cmposiaownn whiah it NO W fA natuany r yNunplsin'00 10ymtralcan to Taud 0 ed wkaos 1 preauna wiem anit is natdii aiN rr A catxmpiound a in afon that is adly coorig 1 >he compound hs orie fad seane th at hast'~ann. of the "'ne'de'ules th siceIbumd with theOtw cpud in ostarn. A "naitatocctnt ompow"ta inhs t a ccaI d iaa an haa fsunmd hin atuni i nQ.nnd that hs n x'ot boeno desgnd by mln A naturay occardig compound may have beniai by nian or by natl. S irtuin oteo refTs to a nemar of the sirrrtxl deacatviao p"lwroteiamiy or p-rofMrably to ite tani&2 m include yeast Sir (Gonank Accession No ?536 5 C ekgnos Stai i(ienank Accession No. N? 0192). .and huma S~1c n~ Accession No. NV 2238 and \A O370 ar AFAI3 sot fbrila as Q S NI N.w -a'd SIRT (G Onak Aitendn No NM O30593 and AF83 107) pi c Ows- (tthot tiiV btso >dad' < the f odioa yut S24 iRk genws t ed "$5T ge " Q omoges of Sir two) IST1. H-ST2-, S7 and M 4 R, and the Iweoher human howroinux hSRIT SH hSITaT, and -chtmn ' at (995) Genas Dew 9:2S$8 ad.ryn et at (1999) BBRC 260 P thiots thatahara nomM similarities wth SITi e h {and/or Sir than wih SR i, sucas those m br avgt par o th N inae present in StRTI and dbsent in 50(42snch as dRT3hrs, oto activfato asixtus a ddehdu that aeMates a sltn by bindWgtt A "Sdiot tebhi" fhinuinhisaideod that inhibits a sa~by biding to it, to 'hgh blood sugar or toacidovis is adl as 4hronk, nersi rmesboli abaoaiitiks aisa i nos awtoaged g blodmardae r ec4 glizm torle.e Dkixees" encompasses bt& oth e tyeI and po U Non h1ttiis Doede of the d aNTe factors ok;fdte eiahid the i g iagos a ar more thain 40 dhes ft men or 3$ innchas Rn ht onn blod presse of l03?S5 amftg ori hgh rgrigliy eI abov 50 nig/dly i fang Obloduose gadUx'T than 100 mg/i or i.ghdonsdy is ISein of less than 40mgf/dl in i en or 50 gd n women. TheS tenru "h'ypadea er4L to a tateor n u idiviiwdax wich the leve.ad'f "Alin t tet blood is hi&ghorhan t marant kurr TI-s ttn iOns resezne trflsa st M nSO witich a axxa amntofks produces a arubnenaai tins; reeponxso elative tte bioogicairsnsponsc in a subject that An "insmulin resistnue disorder) as discussed heroin, refers to any disase or condition thart is aused by or contribute to by nstAin t include: diabetes. obesity. metabolic iyntense, ins inxesiatance syoneasrm Xv' insurlins resine . Igh i gr hypertesion; hgh hado satoW dyNpidemiz, hptxed nai. inpidea atbemrsckotxc disease meaning stroke, coronary artery diseasee or ya. a mdxri 5ntd hypnoerlycem. yerau~ exsnr andor gperiitntiaikt0)m rimped gyh aoswr l n&"' release, diwieti ompi cnary head dieaseamgna pentisecongestieheart ftiee stroke. cognitivse funmznona in demnerutetin rthys.geripheral aeuropathga, in$Optb gemendone 5it osghmesiemrcis nepitot 5yndrea :ypse ive nbproselerosi eratypea of eanee isoch a endometdal breastpestaxte> nd s. kloi empor etans of anogunay, pooxr fatinareprtonese liedlh i h asneaestrrd reguiais. infemidt :areteabr ornaast. polycystic ovadian sndreoo (PCO&Sh lip tompy~ Whlett .rThlhzd dir-orders. sucht as galltones. "hltitis and *&holeliasi a gput osttve sleep apoes sand rspiratory problems osteentritis, and preention and tretment of bone tas e.g. Oteopoross having a body rss inides.(BMI ofi at leas 2$ r grater- Obesity uay or mry nghe associated trust ansn resistance aaren uat additen Ihe tnrninining i in .mean 'ndading but not tnnied in n d and "snluing hNat no imned Nw u The tmt2n "~m(p am idenoP' efetr to sequent iPdedt bewen twa amiito seck sugnwoe. tenm'n two idedido sequen ces. nity2tva camc be dhtndied by TO ~ wanC %"Uticb WONw bOW. N N carntpafig ffaihn Wadh n mghaua tK.'aen 0 Whe aen a ivakent position ibmh mcmrd a quenes ia ocu1pied by thn agna~ base mc atnio acid tn the emolecdls are idertical at tat posien w th\ eqivalnt N occuied by ihe samQ cr a siamilridae (a in staric ancaiio lectrcnc naturen then the moleses can he Veferred to ah s (sin latS)t aN tha porc xpresswon as a percentage of homoogy, "naatity, or ided ay efers to a kianof' the number bintial at ia naio aads at portions haTId b1 the comar stoPqu&ence,,; p;catt at'a p n 4metage Of h gditytit t oacadn atnhe anbtr ot? twit ii'o antr fmine AtNddts(f~' .i sind mby the carompd sceax ad outt uliniet agerha~ms andairoara may be uasd ida1IPWASTA BLAST NTR A A ndBLAST 7anNabhNa a io thea kXUGCG squetaneZ analy~Ss package (Universito Wisconsin A Madison~4a m45 antican be atsed fihegeatt settings. ETREPZ i s vaihil through then Nam-nal Cantor for Bioc~mnoog ThtfimdaN Natmal Libary t'f Mdiae, National stitutas of Bea.h. B sa, Mis in ce *embodeinenat thne percent intty ot two qut cant be dwtvrem.ned by Eain a gap wgfeh amin aid' 3gap m weghe asictwm igeamn uto 0mi td "isinate between, dIe 1wo Oder ~ ~ ~ ufl tehiqe onaaen r desnabd inetods I~nEnmlgy o26 Nompu4r Mahd 'ot ANcromalS Thi :NN SeNvnc Anlys (19%)NNN) 'dDoadsen Acadei PMsa~ dksin fHaenr Bag Cogaan Dig C9fai US-Afkl n augnmaamgra paout, gpS Imtoh Saquenc is uiedoa igt th squbc-h SmitWta nla is oa type of wmsc3t hmthatnts gps in equene Dalittie, Mnnise& Math. Mci. Biolt 429.999)N:i 4 SAP p gram nugne di a and Wunsch aminest matircd ain he radmd to a'igci eqnY ks. Anudaitsve search sN'ategy ussttRi sonware whithnma on a A S PAR eompet:: : Ptea SmitKVateman algorithm to scime seque nces on a MiV&ly para~el camiputer Tha ppe Ja7 v At Aui to k u diSad kad h ands esp l toentt of al aoad unood sequnse mrr Nuoi ch enee .'1iThNa aid eq$ ne ca ,sarh bbKe pmi ao ndiAa ss The a n-rvnoan por ouc tde and o aused ithh me kTcab oy riboncieddes or a4ag thexiot Pykoioutides ay lavei ay tuednedoa sintur and rumy potn any Intm, known onwkno The ia tg o o non citing exagples of pnudhegtides: codin nonceding beginss of a gene or 'goa (rRNAL *nnafzr RNAN desa-i RNAArih ymts, *&DNAembian poltt:aida branched pot5ynckleodd'"sinida vat' isoisted DNA ofany seqnence. Liened RNA af any sequngunc ucl-u add probes and preae A polyzndotide may comprise mod~iid naleotidea.audt aa nhyianyd : wRoidduand aicOddA niogs If pot. roaad orns to fme tnudeotde sium -mnza imtparted befisrr -or dVr tassed of dae tn,* Ix- -4 5"d A p am knsde mayl ba tiar the o aed. sh na by dodagtiorn vOt a Ornmps Te tOTt onmina r y tide tsemia poly tCeOzdde -Of kSontr'm. oDNeA s"ithden'aed r drini m}ihw donouscari intr N giin or w kked taother polyrwdcotide in annaudanee p Adeoind iea ubcr of ha O Cu t trt's w rn a U Or non: Ior denn asbsantiniy hoologos" When used in connehaon wit mano agac equences; refers to s eus vdInchare sbstanwahNy inntical to or sinnlar in segunac with eouiaothergiige n a hontoiogyfd autNT'''Y'N and1 tha~ N' ttnde to' ausd OOOegree, 00 .f on tnoetbiIoiua 3 Qn n immtningie settass 'The temn O' Oe anddto inply a common evwolin of the sequeces. ~To term mdiaCS s aderaganed and reft topprgatdiou$ (1 tineh or snn adent dowa rgakudoiret atinion or appression) of a 0Oespose( or two ain oinwato o&i r I he' tm ambiyne -or thorapartit? I almcts is ataragnize~d and refn to dmiistand a drug~ to a host lif it s admiistered pdor to clinicalman ifestaden of thet inwanted rondtion iga. disrse c .tit a o wankd stato of the host anhia tn tde IrVatment4 i. popylac~"ti e itpotcs rNe bost against devaonng to urnant 9o l d al ~ ~ Ix dN.disk ~cdition1 wheen if admin~istered atler utanistadn th un4Z wa n ted cenasce02 n:e unwanted ccnditon or side effect thArdro>) The tern ~naanaaIY 4 inw in the tat andA exemplary mammaL linclude inauna pdmate bovins pot.nes ca asfnsa~nd rediOZS (e g i d anra The inm3 iolaial3 henIefedIg to a CompiLid is atCemoqZed and reki n toa toun a t of comatmie'nud '4ki.- ("I o(4xd lk4 40 i-fl k A~nhusteoi be 4)orbed by. inarpogPted to. or odxi43 ptehysi~nacl Oaal3abe to a subjaet at pansnt to w ii too! dAdn oiteret The tenu phannacau a eceptble COrM is 1Oet1grdze od ter14 44) rehtiny noroxiw nrgani and org 4i adiid tad i fimpoundkindladi foe examtphe tose con1taind in~ compoition des.cdbeNxd hres The tern "phranaeutiaW aceptab4 rrir" is sieconizd andO refer o a pn eib maer cn i or vehicesuch -as a iquid or oI nh . dAuenm texepienit solvent or eicapstaain mateal, tivolved in ang trvapartingany subject com oi or compoet thereoffrom ne rn or p the body to anotete on4yttta pordewn of the body Eaocornmetr hes "aceeptaler hr the tZe40 0 o flPing tatsl avith the subjeot uompou 4an CutNNNVNxNNNNN d 'not Ayana. U3 te p*et, S(me (x:mples 04n440300 whieb somy serve ohanwWk y scugashOM earners inchdo )a gan. such as tosI gunes cud Smotr; (Q t twhes uchas com4 satch4 and4 potato star d (5jeituloean its derrvea suh as sodi wn .rmboynethyi cdhdosaethv( celh .wlose andsneetote; (4) }owered agasath; )K malt;( gelatin;)ialo (S) eients, such as ccoa butter and suppositry wazes; $ ) tfl&.% iwCoh peanut c otnaeed oi 1 Tsafavwe cit sesore oi. Olieo can a and soyb4a (10) glyianni aS pmpyene gemoI;g)polgals such as5 jeorn orinto maniimol and paljthgie l(l12) est*en, anch aa ethvi cleatoeud ethaA aax'tes p3 ag zi;(4)iigtu Q.dags gis 4 tNh as mansion 1hydrox 3003nd a4hafnum OZ oymsde; (1 Ma .d acid; %pro nfee J7g) siNN4te( sali ; 1N ine>oldn (gty alb 90) N( ph*eshabffe io tad# 4 de7 ustok campadbe s1st 3s plyed in phaonrenutdi ndi4 ~ts i The0 teorn 'systemi dinistraion d'miniseredan sytemical v peripheral adnaistration" mid +admrini$sterd perpherahlf are mi recognisedt and refer to the OamiIsfltdfl ONa. ub jeeGco 'DD~i~i thfpeN Or other 44a040f1 other than dircv itao die icoam nev.s gne dauhthmt it motrs th adn ytn ad, 1h S ;ubledz to mtaboam nd )thert like potessn The emana renterad adshaidxn" and dinis tered pzrriam'y areart c eand rae to in modes of ansatn other nan znteml and topic. adadestt:Oaion~i usiaaiiy hy iaection, and ilngde withku iitatm ma es inaarnk itzaarridah intrathecadintrasapsr. irnatitaL. 5ading tae\r "rapedioeal tanstrda suetneousi s4ectiis n iranartekrae. saheapansa suarahnoid intrsaspt annras rnaxldinjection an dids "Tonedteional segltory seuen$" is a gueotermn a thtiriourat the pi ofaS to DNA sequrees such as iton noal cnhances, and prmots wh nNh ndce r controtra ncription of p n dge th which they ae opersabe linked, intpretered embodhuenig rretnp'ad of one of the r nin gens tinderthe n po} ot otet Seqence (or other rnptional regulatory sOqec) which Uconis the asion o' 110 recnbhnt gnne in a calltpc Whteh a rs sintdended, ivihlat be r adertood that the reC mii gneann:can be under the contr& of tmartinrg se quencsrhic arethe am etwhich are dlihiant lon) those sequncos which con01 ISfInn tdpOO of Ihe nattraVgaXtuur rin om of gee as decided. herein. A."aont is a stali-pikating colbtic aid rnoelerhat transtra an iIserted rinile ai dacule in and/ar aeneehst aellTheh terraIt ititde secters that facaton rhnurdly Lirenrertion A a. teeta. acid molecule ino a cearlle. r iKn of etore that fandatin. prinwadly 56 the replictinf nucleic adm an xpreswm n vectors that ttmionfa htroascripdco andkr transiaion of the DYNA or &NA Ano incalded are vetera that prvie more than ne of the above Ah dns Ar used herein. "exprssi vectors" are defined a poynamcietides vah when renouced into an appmtpnate xmt cel can be transcrdbed and Irma late into a. polepideA An expression systensnav ynnotes a suitAbe host oell cornm d of' an aspresio vetor that n fancton to ytOd a dasired expreao uc "'rativng" a condi don or disasters to curdnn as well as smelitrating atitst an symTptrti 00 r Anditie cr sensea The tern "as is artme zed, and r t arr"'anent of two seaoms or gp round a double bAnd ack that tihe atom's or groups are on the ame sde or toe double bond. Cit nfigurations. are often labeled as (1 conttgtration.
te asA ibn ges to the arrangmut tw a srond a a e bond sa that the iais oroups en ke pposite sides tof a dob Y tond ans corigetse otten cceed as( ) cong urt The D K Ovalat bsodm" 1. t aitd d dreferv tn a bond cteea two atoms where ac~tros r -neated eke-tratadstie bohtnurIt 04f dtehn atoms. and the an otltet (0froeseasod &ironT doaSih &tNesn the fund 2e (f:4tNim>ahi~N5% li&ul repidsona The term oovakmnt bond inchides coo{rdia bonds when the bond is 0 5j a Thea heapeti agentisa'recoazed and afers *de a knt bens iawy that is a biDlgiens phnid y or phamclogicany actvs suthni IhIat loa Ndysten.' ~r~daal in S adet The tiflt thinirne any sust0c inP'ndad rrmuSe iii the} dig riSkO, ttngatim nn r tsao p0te nuttndn ofi de-ase or itthCO inhI acmt of deitable physiai oe entaidevelont and/r"Nnditions h an animal or humnan. The term pu Wnce* as Saxrceognee aD r t alr m rffect in mah patUlady mamiss andi mom pasttcldzaly bwans iaussi by a phanimclogicaly acey substance Thphrae tdapeuticallyreftctive aTnomi n means that amont f Such tha t pxduces same desired localDr systenic eftect at a ressounfble bSnetCI k raI o app4eabl to any trsaumei The fuerapeUt y e&P amouan of Sall sbnem sit ay dependiga upon the subject and dIse o MAnd1on bng tat the Sgt n ag of he atst ago othe sAvehy of th doisase Nr on"k0h txde mer of administimun and the 1k0,ewh can mdiy he dekrfsada hy one ot rnvir lAi ini the art. Foeannpt cesrian comnp s descAnd r etnmaym b adntisterned in a srttirnt arnoor to idreae a desertm i a easonabiebcnoltwaskid< t appicable or cnymatde synlthSa a The ameso compound" is art-reectgned and IreS to a hn hc nd"", Tho lena ei t** is at-ecoginzvd an refs to fmee wh have tan pxly of non-'slperinposa 'ity of the minr imag5e panner, v'ilenhe tunn %dchimre rfers to mokeknehi aate SggpeampatDSh on tna Minot nage hm tpatenr: A"pr A rumcni&d ma a nk b s the posterthal to be converted to a e~ahi iokeride te parmeuar ?The tateria lisoer s arcognaed and rcfh to compounds whichb have 1dentcal eherXIO5 Iotituden but dfHr wht. to the a of "an atoR) It grNpa in.0 spacYo -- 4: in pdartica antimer refer iQ w43sck sennrmmof aiempC n whichare on*sue *'psabl 4<0 irrr imge of oe~ne other ~ Di*emefo en ot handi tafem to tC"s" vth. or mo.m centerz of dis t nd ho imakealesuser nwot 16timagos of one aothat Ftbmtes a Ntve seectiv piteast" icore which produics a patics teroisomaer of areacitn podn h preferce to other possible eoireckoeta of that trudent An 'e oa ialeive gnoesa is One which fhvooi pendreNOO of one of da roo poh entimeW o, aretetori.it The term " ireglaiser2 a t cogniaed and zeimf to aannd whkb hase h sam rmob der sm a n rifiVr tin thecoi001w'y of he tKots Acordly 30 he N. "N ctone a5skh dtrnd , ydsigificn t n'rae n yie d of aeri erag 44 a'somikloma r r The~ term "4npiserd a ar anguised 'oand re to o cordes with idoncAi vhcicad constnudtion and containing more than coantareamer. but which differ in catiguatin at oaKy one~ of these ateoceters< The ternEm is aN tr'cog" t ''din cadrtainbo diment::i Efl :< ns h do<sez of a rg ~c produ<er '$0%' oftt ha inax raptto Or fibeo alheraveiv th dose which prodocea a ir neermined .rsponse in 50K of tekt subijecots or preparros Tfha tonrar fla is nrereognised in certain embodimentgis. 4meanthe dose of' a drngwhich is e i i 50% oftOst suje h tenfn 4 Marapecue iin san ar55cogn, ized term which ree to the thetpouaic ider of a oh dbfd as LD) NE> g the torntrnetenitshyw tionAhip t 'r"(R' ar-e ioand ers o the rvav b which aNherng th molaular simotore of a &ago~ or other coimound alters its iotii cni Ky. g~. it' intecartreoo ith a rutetr (ensymeX oruta i id et other targre and hlike. 'll ten alyhds~ar -econzed and refers t alie br-anced didkn n .o .1tLyt4 Ta wak M& OW A&N, 6 gru A'k 'AW PMA m -100.O SerVE o srtain em100 wmI phtcgr~sath raeppC~a linear Or branched ad have rea.1 to abont 20 carton atom rh: ter aai is arsonioed and ind des rahned alphatk grops An hiin s nd h d*YN~ N ANt .alkgla g'.p b a N $ed v'i elky gr up ey a'y ( n y n s'op.N.4ia)t a cC gromp'ltvyi a ub e 'y jyi up nd cydoalky1 substed sk grophn tos in its backboed gs. 4C fo(mgr cag ta V f :ncled ch"uA and atnav about 20 or fw kalky f 3 w b 10 c4arto atom n tlhejt' In strtcure anaid aftnavy about 5,6 o e c aons in heiong smict re.. the ton " 9St 1$so definedtoincide halosbstkNted akvl the term easariky arteeognized andefer to agaikyt gr'Vopsbtue ha styi gmrptic an4 r atomoatie or hetemammnatie gmip4 AThe ts "alket ag d 'kyy a tnrvvigheyw d d tier t"Anyt aliphattc groups' eAogu jufngt a~~f~ndN~ poht stitution tO the dkyls described atnove, but thc:n-itwjptze dC una oubtdple aod no tpsodel unleof "Minenonac:ain rsotmisa ipcnIfid< o'er kyf'roefs to an aYt gkp doned ahonerd ha inn tM to abet ten a but ahcmahvivly Thsn O o to bou QtttXOn as01s in Its baokboner 5tttcQti~ tih iso. 4 twa aor o~ef ttti lwer aikyny" have. siojiarl ningths The ten "~hot matorNi aryognized and afers ean atom ofT any t 5mnr.t 6cher cd arbauu or hydrgoc. Ulrative bt xatznrusaido bron, rditro e ygee, ph4p'r.. ft n se-enm The. tet rr * . anegie nd iented a d aid OW "m'sinl arOmeatic pse that may moinde froni 1ct fhew xir hetenatomsexmp, betNe mapht aneanhrasenm, pyrene p"SUmC Mna, Ohohnnindnl ava Nhanile I.WWt"" ''\46 GrXMPO baoln SAU 'y tazohe yymrmalepidhi gynat gydazine and pywinidine am tedike. ThtugoaryW aemeya l 1* Cat'S0 * aet-o tit0 Th'to taoatie. otg Ia st >stwo d at one or n ringpT at 'm ofh "'I' iuena dt- id sho 4fork. amp aln,1d anik:y. alkenyl, aIXk ni cvdoalit hydreayg idkOKyA, szn* raer Plfhyd rnaine) sulfomranidt, imtone AdWhydZ estern hetevalyl. at matic or hetereminw moieties, CiF 3 7N. or the .kV Thetenr ary4"eisetor ire rtv oyrhont VgFy--m' having"' wor mor oybc iog inwiihh -. o r mote cEarons oe romnron to tWo ad boring Eng (t.hd n as reo fused ring" d'i)a lenat one of' th jeis amnmado e 'the~ tNcyc rings mayt~'h ttcyfloaikyis gyln ortan yelo d hynyvN ary s and/or betaerlia.
Theens gie oaand Daaeaktgidand rooer to 1qk !, n= 1,C disbsttutd inens.rmespeedvy Faor speh 3.ames 1 ;itetvyihede n nd pi eimt lbenztcne are synonymou. The ter'ns helemoyvl r hdtamcyeli goup areoanocogised and Tvw iv to about i ethedn ain tr r ahernatiey o about t.-Mbetndag ring suaune rnctude n our te atomszo flawtoma a miay he be Ueteirxecdyi gtronpa ir ror oxampk thiphene.iinheeia ya iotieorts aa neo, yridin rane eyx chedian yrdske indCizn isina int) a4Or U'U quitK ntx gotinrto.dh cahhotnaphatyddie 4 qno a nidrqu nalnt bmo. p strirwz: par\azo eE::Ote heNaZtO ntiEh htnimie, pyrrotdia xrthe, -- ndane. el piednei dnysa anea, nctoNd ts Sch ars ds and pyNrroli dun, s us, The heeoyclio ring mnay be ubad tted at one or more poations with ah .Aastuan hyrNo4y nino ar xahydrkv niien, aty. raday-x, pos nt haphCWV c3wo:gt cbol sil eu aty, kr sulon me aldehyde. eter a heterMk c n v au tho-mrieyl Muct hesruoaert }2z.*iN , o hie The term '~paiycyP ty p>hsya"J agrouniare anrognize-d and ret to two or moor ringae (e nkayk e lokey cynalkynmyLapris aador heernnydyhL in wich two ormonre canr s are Conon to two adding range th rings aefIsed dy!Rig its aye it~ thW~rmre o dnea ans of to h egs of the po vnede ma-v be snbstitu ed wi ath nb dmtinest as described above as tor exanmikh i gun% hjk at-\.j,%y a kyvgoyeaiyL bydroxyl, an ntro. softdr &Zn amode phshoae phspvlt caronglaroxy .i ete ns its 'Yop.e ANp. o dagh :o vdtvony \ 0 tou 0 'dhydte et a hetrooydalvl arnnl ortro ad yn.o~ k}&. lCN.qi or ho bkr u N,' CnN rh Mk, or.
inThe renn taxhecycle is ar{TO"AgAnsedAp -ndmrfers to am 'otoiornmon-arrntin ng in wtb eachi aom oleningis cat-onI The term "itino" art- cognized'\A ~ad terem g 0 -NCte tern "Nzaiogen"i t re-nnfred and rotoen to M C, l or -1 thetnra %dularyt a ii rt-r enied and me'm to -SW ihe terna "hydroxyl"P means -(H nd the termtndilonyl" is atrecognizedi and re8er sdS Halid? dedgaates whoorepn wugin of Mhe hlogene an~d KCaton anudXikina.. Th an MOD The -,enn~s "ain" and "mint, wartxxqpL,. ize nd rkdfet w btinuhene and esttute an0es ag myw th~at may oe rersentd by the geaaza aa; R 5 N N \'"R4 32 R5, R-5- a~ hywgw. kyl. oal'ry (ir or' KY? ad K)3 taken tagehe r with the N atom to wh they ar d aonplew 1010 hiOtQeyd hav f 4 tu atoms in tbe"nr-1 gi Rut" art a IydoalkyI a conkdrnyb a hetameyr'e or a poiycye; and n is zeo or an integer in the range o c t n cetai admnnta y one o RSf 0 r D 5may be a cattnAy, emR$X RSI and the trogen together do not fhnn ande..dar her etobodirnerda RS0 and IR3 (and opt on dly RSZ) each inepenty Ireaent a hydrogena asik. aiken (C rAdt.ia. Thu term "akylsaine ireludes a aminegroup. asdeid de e. aikast noo of R5:0 and R31 san kaf gma {he Ictem#4 acyh.. d" nt e'i an keeognized and Rresi a inoiety tat maey beo reprnemd b he ge. aonuk NR4 wherein RS0 is as defied above, and $4Repmnt a hydroge an alylantadkonyi or -(C'"4 Rh6I where numad RGI lrt IS defO S..IbO ve The tennt aidO t 'it l ai <0ecognda an amdnesbatte~td Carbony>1aad intue a moiety that n ay be reprcnented y the .genera Romniw Rul
NL
h 50 d R ar deiaed above. CMna embodhmenta f anade may nt t 1ti ennlkyshit" restemto a akv togroq s defit~ned above, 4ving a ot of Welkyl $.44keny1idkyn yly ad CMH&R1v rein,-akA m Z6- R 'ukardnd b etetaItlY kth 1phd yh t h nd 4 ut hde rk The tenr ' arbony is' arn recg nd inrlades such ade as ea>' be r'esnted by the general tsnmus' 0D xN.0X50 RM whein X a isbond r e alS xyge nr atSeolaR de y an i sn aikni H tR6ior a hamanli y avept bl At, RI6 repres a hyogen, an alk4 an alkayl orKCU5R6V where and M t are defied abovrx tWho. X>U is an *xgen anm or16 s not ydrogun the fnada reprents atr ese Wher> X50 is an gsadR5sa eadabntemiyi eerdt rein as yan pricu & when ayoen aee foem a totsto _ ornis. la .ensat wh4) th ea gen halY N4f.4 th sa.'e ennthkeps~iaced by eW hh sp'ank a "thi0k4y gopVh ac se h is a sdiernd R5: ir Rs not hdogen, the formmda psns a "lhoestnr Where X50 is a u and R35 is ydrogendthe formoha represens a aihiolatexyiic acid.7 Where XS6 is a Sufi tand 106 Shydoesn the firna rgeesenta a "thitibrtt&"t On the otherthand \he54 .X$) ( fa 4n abo 44wh 5 w lydn".S Cc~S. bond, ands a o nyd gete ahoe. tnn repasst> aktoatap. Where XEd as a (300d and RS3 is ehdrgn ei above irore da repressents an 4 aadhydC'group>. The tns ex Kdakexy sire forecmergusKKed and3Q take tn 53ak4ytgroup, as dzfined sove baving an xygen mdical atted theretoox Rp3rsntatihe alloh nmps nhid~he rneth h pu d the k An " r wo harocarbnhS a y Skd:by\ an xgn ari he substiuent of an adkyi that tenders thailkvan ether is or rinsed an maoxyv51, mRay e apst by one or Oak OkY - 4 ixikyny ;OKC1} 4 t whore andd t.u a3 tmeOd N Tetr suitfnatV" artn recogdn d and reers in a motety that may~ hi representedbythe generlU$dh hIkhR5yss an dewr air. hydnarn a42sn Ayiydalkl orarvyL AA ASn " itais meogized ad in RMdes a moiet IIna Lemeten by -plagenbOeraignkr R56 a SAW bov7 The~ terna tsatb tnart :rtt ee e n nids nit htna reprsndlthe geerai nnral iu'ntkin R5 i an d maas dennex The knn lulameys" is artwearaoged ta riefrs a maintyV bi a beseav repwe~Nted h.ite g....rr c in whnch P2 & o ne t the toil ea rg: 'dag'err. ankc er.~ n Va sir vyy egdg hetaracydvL ary at helemaryL Thei o and *kfk4n to a m2iOty tihzA mnl May beht repwayntdby ire Ther en *phsphryi 42 trm ogized ad may i ge&t'h rerse by the -wl~ruia Q$C5 xa, 8an abr S.&dE ~ht Iy o XQn \Wen us to suoeuw (x>3 Ok~y th> .. sykryl g (ou otho. hosphteyLik enny b reprent a by 1he genere U1mmr OR9 OR 59 Whrant QSO and R59, enhneednl dedrad btan QS21 nerea 0CS 8 N hr S t Dh' phshoy net a. a poshrth. Them t p "prshoram dite 4 is a~rt egzed and ravorpeetd aeeea N N R50 K51 RS) Rs WErein 5 RSR5S1 ,aO R59 am adined abovet. The ten notshanamde ei athecognized anr e be rp tapan in the gevnafnmtaan~ R6 R0 K -Q5K5$ ad 5 M' RCO 5 Amriogous. 'miluikns aay be oade to lkenyi aod alkytwi gyoup. -o prod t exam gainoaikeuvys amrinaikyss, aonidoangs, amadai:nya anioa~ronyks. lauhttbyntl a hoa~nys thinedkynyU. caronysttbitted dhkstora~hvrik he deIMdn of each expression, ey Alt M. r, and. tse 1ike, wvhen it occurs o than onek in any sThruCi iteded to bt dedent d is definition ePsewhen in te The s " odeikT is aricnised sUd a&ueso a y havibng tsubsts seleto ganop attazhed thereto, Eiezpry "se netherC* wh ichi uays her MSanietd on Vb a ta s'tected f (4 8e- k ISekamen &Seayt and SedC IZZdkunaid Roaong l dai ,,w4 .so. Th 0nna aidy sy n mdy4 and r aA."yfl aae rognoe Wkdi rensr U nutorlh&1,OAnstdaid pulqnxlfn eehnndon n to onet ots &Mctnv 0 tiebotand.e onyl v gr'smps, 'gtivdy'. Th) terms tdiige. tosylate, mesghaVid\ ' n%2Othittre ao rtes'0 gnizesd and ref to tit meN thnSeNVonW§V 'osoteounstdlfan eser mcthaotooit& a e esaten~d rtaofatombt uesndfonate es*ser: octionaoups''$ 'ynd ondocules that contain aid soups, rstiey. The ahbrevoad a M E it "F NT an sd Ms reprsendth thY rphlnyL trdiluomothanesutany. nonaf.~htauelonyi, poksavindsufan and inswa'e bnvit epetvel A more coapeenivit of' th abbN''san unised by mgany ebest of f''txk dsm'~ 'ats in a t adpeaoeas i hfart ssu a each al d ies handdgend eil ''wih l i 91edl rQete itab snie% ltli I, o)(fCtatcop*todS eotanined it COmposi bos desctrbbd herein stoy eiset iN. parti gee'&hn A it Aite tts''d f(Inai ddl ildA0 cin' wnd'inav us . "op ~enti'. Cotmpci0d herein ao all $s011h :mosnxta i5in is. ta in a "tr and $'etiondmr a."diesnteam (P'Pomrn (tiscrmersh as' mi' ixtres thereof. anld their raixtuns therent.A& 5 5dditionasymmtfrc eartont atorms intay be stresen tin a aestunt te a gakyl gras Alluc en a we 11. mi t hz%- hem ar e enpaed herein. sa paflieac aaiencr o a cVp is deniedk it vahe prgared by lymetne aynhesis or y dean w a dhrai ouzisary whre the reun daeoei mixture is separated azdw tauiliry group cicaved to prenido the puedeie ennimesAtmav 'were the niSlC46e contofs a basic tinn iu gmotp, det as amino, or an acidic inlai jgr snobh53 (bXykdi ~asream d san4s arc ftnned with an appropiate optenva'e ad or ase 1 folovwed by "s n" of the diatcriamer thus franed by factional cryatanadon or ciratao aphic means well known artandabseqnent recovery t>fthe alrl enonoe t It wild runderstoodthat "ubttatinnr abittad with indca he anyicit provdao tat suchvo ttxdton~ rat aceordnct tthi prmtied vaence ol tbe tubtastd tane :d (tdustat and hat esb ution rsutsin 4 a stab'F c puNdIt et hich doesnt $puntaneaaiay utn do trastfion such as byragent ntdtin elitaa ortootem reactdonl The teme "sus~itdmad is a>lso conmpated to include al permaisible sbtituente at organccopounds. hia had aspect.the permissible subtitnenfitst lnahde aeyio and cycio branched and ubrancheei carbecyclic and hetero1'i> am'nttc and neonamtic susttant*o 'orc'- moN do ~4 lhs"iv substiuet inckaderfora eamupie. those debd herein" above ~ he pnennissible -uaien n be one eiore~ cndt.e same or different for ppropriate aqane components £ktamrtma atzas nitrognar have"" hvdr'ogen subttue ka2'nbentv+permis'idhA,;bst.unt4o~s f. tgn O Aompounds des'xcde erin which eaisiy the dances at'the betteoatons. Cfompuonsu e not intended to be $ nitd ay tnatmcr by the pennissblhkrsbtinreots ogrd enpaid 'iTh 'besul oh atsnts are identhi4d in acordane wih the Peindic T'hle of the that protect a poaentiboy reactive ctuaod grrup tr undesired chemical ttrannaon.. Exanmpies of" such protecting Erztupe include esters of en)o i acidse sihyt edhsof akowlcholand acetael and actale of alaehydes and k nMe respective The tidd or ootetcti reap 'instry has .... n.....wd by, (keneen W tV.:> in ">enlaia ''d agres {'' d Vteks New York. .1991.) 51 Thu tonmhydn yi etmd gr is witropdid and rezs tothse gn'aps intended2 to pt O~fla hydmr group agai dr auin ryxahlie prmdIre and iO K d ei ayni ben=yi or other stdabl esters r ethers gmrop oo no the aAt. T'he temnt "exybpoeteooog gmauptis attacoied an d rtfers to those groups irded to tidota edeyhae Od 19Ut 0J6 such the tennlans of n ammoa ci or peeie rd 5cidiC tX hkditt oephei *:b.iTht~ aganaslt 1nesbrate reactions draigmheYO>:c procedures and ildes t Exaples for prw ag gr tor earhoxyl 1mtpsiVeg o eenyeatr cakohi cstr Lnittobani estei, tnoftvi arima eer 4pytvi idyhnWh"sten ndto like. Teterm kmnine-blockin~s yrup~ s mrooco~nized and refesrs to a gstop wshi ll prevent( an. sunino group he pti paii a ta ctinardied out osz seie other functionvai rsop. hut which cant he removedl aeIm the mi'n wnh des.id Svch grops are du d by aCih of G n Adat hie ab Oe sod hf trlond T w sn insa (jsge entv ch 2 (MOAi ad, xenum Press New ork'97 Exampes of suiaise groups inchrsde soyt piotecting groups such ask to thristrated lOmykda &ny<steeyt tnOg i htmebKisacani.methbxysOCrcn r hmgl and sttbsttuh be.yl% \t4 's 43Almnethvigvhctyl, x tbeo. an'd tripenyeusyqr dos' ttO$4n 4kemo funn XCOR where R incre suct rgrovp\ (4 sdV m<' 4e1hy) prok ' Oppyld ~oN h letlhy phe >erh. .isobti. PITuty Vmt Vi flyl pheynt b MAs p obm 1 artrobemran sd2A-iemnehensy: SOVI groupS M and hatsatuted aeyi such as towmy acti, ehioroaetyl, dieioroaeetyi tdnioronwueyy rrnoroace h etoy4 and .p menhxyteoaoyAt nd Other goups saet as meransuyi, ptotienesutan NO, breobeneaerP fod peniitrophean~yli. and p-'eeaensunhy1anminreoom{ heebrnoekingropae henvy Q(CL2CM sytI[C(O Iuor STRQ where I is C 4 ~ aokyi, .haehy or :24alo~ssestheC 0
-C
5 afk'y xA oaieu, hn pretov' goQUpa as fo aei carbonywlbi~mglo ChQo asnd aliphad urthane possdag mup such as thtlxerog GVoc) or 9.duowtytmetoxyscrthonvi The definition of' each expression, e g. owar :aikyi 44 n p5 fnd thlke, when it ocrs mooe thanne 00C an5y' $ttutttWe is itttended to be tin4Xpendent of is detlotirm etsew hee in the srme sutoce. 2R1 Tetenzn Wsket-au*witawng goipiss~ arbreco jana and refeirs to ho te:ndew of n substit In toadimentnce eetron' twngadghboring atoa htm W we SobMMiMtM i: elettrdgCM spectO udgOdfg nt ena. uA nation of the lti of' poruko 'ith gcap bihty is givn y thi mtt eigma (oz ount]afn wec known canstant iades rihed in any rtncs for instance March <Adsmgz tI ne251<9 (Madiaw Eill Bock Coantn New York, 197T) The Haamet contact vanues ares geneally Negathea elciendn inrungsi (P(# CeA6 tb ii wnd p for k a withdrawing popts (#kP) 03( fbra in giob, o() Iiatiw para substtution. Exemtpiay detrowedain rowps tcnn niar , trnnyi uayt tidh~norneety can, hieddr.g and int, lad hmplary ln donatin ps ndaude oaina th anad the ke fmu t&An by rding tt m ty (Sd 8tsnd) a iud ais (hd AMPE are necesary fr resatrmeatd mohiamdo (Sg examples 3and 4 Mut actrs snAtmA fAtm S k5 r nd, A d~eaul 1)ad thateratcd jlke other AMPaK tacdt, can StIWmatanty~ adds~ iv honin0ipo'Cen 6ccs (rLxmpe i. fiemplary str r-actvating comikaards h that e tarssitrrir are teOibdi MYwiz e a (20X3) AtrA 42$ 191 and include; Awnxamphie ranrol 3$A' 'e'ra" ydroxytmrstilborn) i.aniridi gisin (4 f' hrtroxy hrdealc) cr is-tin 4 S 4>'e tnhyddnOXeVIIeWNh qr~tcdnint4to.hyoxas Denfgand (0 nbyshw~nartthgatbe 314M Scosida anna'dib (3AhT\0Nd4 yd en) 4ffnthdaycaonChac $4 IT rhydoxyhaoe 3X emyrxfavene ' -r ryavons 4 lvd4i dshjoxyfavo"2'.vdhd roxf ccne- uri .ai4 Ptbhydncyfl ou yhtane 5Bydox -rue *'oxvftoce (Nypaxy 7rit2 4 4K );Gatci (HyrIy Stc TW); ( O-Otschio (Hydroxay Sim: 3,334') ( 4 'V'.e'it. 211 (liyd~xy Sites: 3tr' < 4 ; if9fpenh miyn iAde.len ($7 N4 (rdw 3%T Te4JVydFQMyfao.; 6}idmyiin (2 Toiaygliwore); detihth Aigein (54AydroxyfavnV 3f2 4' 7t P(,.n a Pand7 lade (231 benyeroyihty~u ch add)O~iinf dl (ao aptn;,cg--spoy "poetkeI n h"va (()~a~ oaiy2dihyd a N 4nty 2And~4Le he4yr'NN4':- N't'i-5 nes D (Nheovydgeny diktmrobooawymino) cvydehexaneCll*A I U3t;E ((KP2-(4 2,4ikU Pyrrolidinyl-4 pyrkdiySj-'pipmiy)ehyv 4 >diyho t2" 5$ treameLhyVI-Habezopyn4~K ol2H2CI) Analogs and denvatives ter~Mos cabae uased Ris $aR SRR AN "Npses a&korai M~~~i Tpesnt OaNnt"
R
1 R tt sts a hivz 4 a kyl, aSeny lknyxtW~ H aioanaido tdiaxwht alkay]..hasa~lkvidev~ i' hydnine$3>C. ($ grota4gosyd r is 1) or 1; 4 prond that whe no:g( %let and A am ORi RR ., R: R u a'n.1and . ahuteVy a>. i a. dele uCt. E9NiNOut ropy> xet or carbon; weA B3 is aikl. fo rido@R 5 anad are ndboth On ; 1n is ORit a4 enea o.1.a an R, or R isnot of ant RA C' t'eav oduartnatoetnnan en a oornpmo d as own as olvnmda n h atndant definoins. Ierain the tis . In a fairt tmbodhwnai, Cthe copuds a compp Sd As u um uila and th 4 tb dnt dtn ideuais, whin, dh e is .t a {Arther ocmbodd, too heoropound is a duonnd as shown as fenmshata thtadm dridna. whrein te A Da is ethenyt In a frit embodiment, tho mpond is a ompnis shown is fcanl and thw e An btonla I00. wh the aturaWa CE c'r( c)C~HMe\ H In a nd rather emfbVadimntAl te emnoun ise comound as shown as fnna I and the 51tendant defiaddoms, vdherein the 4 is 0. In a fetiher embennt I' omon is.. r oon a.k. Jk5S shown as Itmudaa an h.aedi as~asIa detainsa whewlin RK R. 4 K4 RUR, RY i nd Rare I Lin ta rather entodiunct e cnanound s a saIopound as shown as horua and aiw stedam na mv whe1en 41 and d a AO. u a father eitodTnontO the cm0,nAm is aOH inoad ant asmbint the a oond i usas d ettns hen K a oRmia and ar R tan aite inodrent asnrronn ittC itendsus deroins. WherNIin 11w i. R;.4.,and RU are OR. Ina ia dne dian t e apounrd j:s a co'umand as shown as fbonah I ad th eaeda n dmitios, where R' RR' tr a 1 n R areOH na frher bodnment the copound is a pou nod as. down as f nnaa i and tha att0dn V d A nations. whea K 5 and iV an O1 R is C^ D ghotide and R i OCH i a $ her ensxAmcngthe compound sa compound as shown as fermin I :5d)4 Ui enan de2 tn:r*.s wheidhR is OH; RI K s Of -an 'Ns anod the is C the tendant dfnion4 wherein it is 0' .4i Befeny; and R 1 R s K 3 Re, R R KU. Ian ' rn tbn nafne nhdmna copund is a eoond as shown as fomla Iand the s ~atdat detfifens wherein ri i. A4 is etbenyte ad is 0; and RK 1 , R K 3 . Rs, R 4 4 W. RU and K'- are I (Maal.e in a ftrher enibodinent ite snopond is coinpond as shown a tatrthan~tud nathenae dianitions, whaemin A>; A-3 it eA ; R, R andL Ok% ax Rnd R R . s RR and R ae H (resrernini.n a frthr ambadimeng thoun ard is a compound as shw s atnt de.i tie awheni 4 a, (i hend R coppmm ' the t>ound is a comnd as Mhow as tforana I and the tIkda t dShitins hLenin a i A athtyl Mii i o0;XR and .R M R A R -R , Rad R a R are HwytHn) iatrn a fanhardinent the m abe s wata as shown as narlw ivamthe auendant deti tioaawhoeain 1 iX J eihsnvt; Ni ml; R . RlRbR H>nd R>.ars Ot and R 4 e RV R > R an R se H e 2thhdoxythdene) Aa i thcr eatdn dia5 ceopoud is a m d nas iioni I. am the ttndant denidhons. wh ee edins 0; A2B is .thenyi; Pe and0R' are R5,1, is 'XgucosideRis ORt and R, R3., RH>, and. R' are H r itapnthhg .1a fadhar emabodneat, the emnpound" a saflppond as sown as tmut'ta imd theZ asdant eations. whetnina is 0; A13Bis >-"henyAI4 t R ici it 4 is O D-glueoside\ I itt Oitt and 1<, Ft. 1 R R Had5 K are H ' Cr NT' and (deO\y knponnt IaS .UfO Cine embosamen. ~NAAa comOund is a ompond as show asf attaIhand~ the attendant efta ennheren a is 5; AB is Cfi(MK)H(Me)C~l; Hz . .and i at OH: and R R R . and. R~ am&DA i anothe tnodenn siunaa t .Thtna cs pond is aflavanocne comspound of Annuk> 2( whene inepeata seM~d ' XV rprst C daeaeO NR c're 0>; and 0 X at reserts CR0 H or ; and Y represents CR or N fi a fhdher enabdimentV the compond is a crnpond as shown as onnuhet and tnr attes(dnt denins eihein N ±Ad Ua bt CR in a ttiniet anZbodImenit th c1aund . a comrpsiand as shonas insla 2 xad the ateiat dinitime weindt is 0; it a tirerhaodimuste.. newtapouN d ationpou t d as *how as~5 flxm'ada 2 sad tet autndant d;aitina when M is now tt a ai b t he a c " p< nmn s comtas shown asfAtndn 2 and the attendant* deitien wherein~t Z ( iii. furth& embpdimerne the cKmpound i i coge as shovw as fndak 2 anid the atenden de ar wherein R is H a further embhodimnt the COmpound is a compound as hwn as fenmnla 2 ari t4ann where n i is , { f In a fudher mbiodflimet, heS campond is *a conipun as shown as nai 2 anid the ariendant drenous\j.erjn i? an ester. I a tardier emabodmnh mp a m DH as he a h adee ' om. . n a Jpund thmasdan ful 2 4 ,dthe .Ittend den wbagheta Ra, F, , P , RI Ri R'adRa a further raatibhde nmfth comp round is copow as shwas forulnia n rhe attendant dxA )A .05R~c'a. " ~ ... k. s 's.3 a\4~n d 5Th aw... i nr~*r. a 1. fr pound as shownosnusan tandant s efen re2ind e atndl R".4'a, 4C'55N t n C are:O iirhrabdmn the hom a.n iste rcmpodind si shon ars n.isa 2 emb e, tnent u Ks aQ tonound as a a ttenan ddaanu 1Wher, RV R R s ndo " or fnama Al1coo OSAU it ar fd tA'th " mbdret~ h amo i j compound~ as own as trmuda 2 R0(R tR .11 R tdbiria' .~Rs and it) arc(1 OH. X n a f~hreenruathr compoundn iii copidas sow a fom andown au aKenini ad se wain Xn akin 40; wn ore aln i 4 R. A, RILwad Eit' O't : (iR d .are anaeoL ther emoiaeniah ail on sis ac condia2 as the astemdan 2 ad th ard dadetm Nend n( w-a Nt XndX 0; C is O an and O 0~i H; RNR i 0 R2nd are O iti .'t 1%R R R and Rs.i' 2, R 4N ptnahyrosyvavn}. i a Atdeer~nivnodinua te e compound is a clopnad as swnas ibraa and the attendant delinitsons; wherein X"V at CU;" k t is Z;: and rI IQ, pa adT.rn ad Rt & 1 andaOra H (enpaciiOn in st furhsmieatnenathe omp d und f dhown as femmau n 2d the stteasant d rans wharein X and Y ate CU;h 4 i ; ZL and C: R" is Cit Ra, 14. l' RY and Ri 4 ar C and R. ", RsJ, and R ae H (gaoca eci In . fur mbodimut. ehe compeosnd is a cOmpoend as shown af 1amuda i and" thee aandani def1~ihansgodrine n adra igM oi 7 ani. O<. ; A9)vino R '~ and Ri ate tGHL sid R. k" t , and yC at H (yense~ aae F4 M ' Al yN , RHP. R 14. '~ R'1< RH' tR,': > and R> present t :saniA srvb headarylhv;. amr~ergaktgidei N%,SR. OR N(R 4 sorebai R rpantsb P Tey' or aryt re its HQ NLH or .8; 7 eop int CR. 0. NH9 and X resents CR or ;and Y ropresants CR or N in another mbeodinntia a. sii svantinghw vcompound is a haiono r ompound cdf In.rodR M: 4m4 whten haledendy for each occurrences. Rt R R I R R . and R r"present R RMyt aryt iar Y14 aLar ettnIk, lotionyhdad dNk SR OR, N(R) or c yddXV ir ibstor represa I. ikyl ayijebttaryldt hwi ettroarakythftde~ NO SR OwRNsR orcakboxy 4 KRr eroseree fl dkyl nry M represent O N or S; Z epresent c:ikO C >x ar n b a benefeatheeUn nth Ompetud is i a oonscnd as shown as anwta 4 and. he a &endtt a tdtnitdons, wherein" C a a fher embodiennti the:;p-ind is a 3upon as sho:wnj as fannUtand dhe attendat ddfitisoas wherein X is CI2 In a fther an aim the compound is a o poass as was foninsa 4 ad the anit> detanidns where Z is K b t 'modent the co inond is a rmapozui as shown as fanuda 4 and the aten a dwi In a fWurtm&4 $er. etdim~ent 5 the compound i a compouInd as shown as :famda 4 and the aidant astgerein ItRis K i a after emaibient the CinnoRd is aCoupound as hnon 4 Anda 4 and the attendant ieS&e ns. et t.'i OH. In i tte embedKnOt lteS~ nnte &5 Sega a5 ShOWS 5s .TOnWla 4 and thei attendan &di kt ern R, R, R n. Pt i Rt R and R It , aRde mboditahe o)und ffm'and a w N tar O1 Ita faher enhedimentthe copoundi a oatepud as sho n as tInnuda snd the at1endat dehdtors hin R R ad Rst>r OR ha Wa'her onabodtnwnt the congxamwd is a comnpotnd a shw as foml and the atda detiCtioS wherahein RP and tre OK. in afturterembimmeitthe caumpo td is; a compWund as shown as brnntwa 4d the attend deihdtons, wherein aK. W , ind- k are O in a Wither embodhnentthe Sanoped is a copound nas wn as alnnsn4 and th .tdm dd s'nd . O4In a fthr m abodinient the cdp5ond is a compnnd as Shownas foarrda 4 and %h ttedan dAioS' whe in it, vR. R4 and > Q in a further enzbndinent pound is a compond as shown as forman 4 and Wt ttndnt ci tins.hoadn R and R are 0.1 ina their the compound i a Opo shown as taionda 4 and tinnt dondiions, berein RK IttlIC andhir PtmOR inbadhrer embodinmen> be compoundai a compexrid duas shawz as tonidna 4 and the attendant defint as. wheresa',v R - R r are (R L,- a Whan mboin the tcwpntand is a omnd as shownas ferna 4 and e d d hwn a 4 and the nhtndant delindo vhren PR und R sea K ni a imher enhat tha ompoundis a vsnpound ah e atia 4 and ith sandant dadinition W heezan R , R, iand RU ar OHL In c e b.dkn.an. die compond is a compound as shown as fenmda 4 and the atte-dant Armaion w nin R and Raare . 'ater \abOntthe Cinpund i a uds w, fMad 4 and at n n s i , OIL La iaher emboimni, fee on d is a cmpotnd as shown as fianuIa 4 and the adindant definitions, hreina Rea d RU areAE 01.ur ats'ther edinent, th eunipound is a ompoand as Sown as fhun 4 and the attendant deidon.ekein , and R afeDH. hia feathe tinanen, the ceniprnd is a eneipasnd as se as thuta 4 Aii the rendant defnitens where R R R and R1 a §H In a foteQn eIodhennt. th ann s a comroundss w asn a tfoRa 4 and the -atndat de nitioswh'ai Rt is O. in a indr enbodiamnakthe compound s a enmpand as shen as to nW 4 and te dedat daton wherein R L R* RU. and R are O in fr d tanthe enipmpnosd a conagmd as hown as fVhada 4 ad twherasadant defna ut 1herein R>R, and RUgO &vt II a fhaher embodina; the oped is a compoun shown as formua andthe anadant detfiniiona wheiun , RR ad R are C91, h a fui rth*r mbodiment, the cnpmd is a onpoand as shown as f1bnnaa 4 and the attendant defiitions whe-inXis CW, t'> hsa 2 is OMi nd R R RK Rs R RN R d R, d (shwa) in , .Thuss eti-dient the connpound is a cponda e kaancxtn deisidtns wheren XN i ( R O Z in QTAis 0;Rx . R , and TV cart 0-I watt E. Re . lt% P.' 4 .end '11t~ hia Int a ether enrixdid . th cpamnnd is a cox. n 5 :nmd as shown as f -ntdi 4 md h auncdade doiasuho whain X i C Rj is absent 2 is Q O f is O; Ra W and R-& are Ol: and Rhn ad eaeH(Jg tethdoyfvnki diintos, )t.wrendi ;. i I IT i 'abaset Z -i 0; he isO ". 1%.. and R's are OH; and aRt R A 4 and AU are H aetdteo haa.ather endaoneuathe oenj nd is a compound as shown as bamada 4 nd the aCtendant dentine, wherein X is C Z: ' I o.~~~ i" Mli Z~v 0's N Rs ~I bI t ~ ~ it rahydroxyiDavone). hi a .nthex *nkodiment the cpn d is amp as shw as ersaiX ta 4 Wrtsi Mt*Kd ,at definiions, WheV5U X is C i O; is OM is R< v R T ad R' aM O" ; and R Rx R R n RK a (arcee n a eb nt the cmond o. a moud m o 4 aXd nte a M a detinitons, wherSZi X i Cit R" b is losens O s A Mi 0 (); It, R R W, and N On and R R :. Rk anr 1- 1 a i u, t am. Odimm Wh cOpUMd is a 4omouInd as shown a: rat 4 and th sent d whri X i: C IC is "a; Z is 0; M i 0; R I ad RK x f44 and R< R% Rt R. ad R. as Ht i a trh icmpound is a Compound as shown as formeia 4 and ht attzndnt detioas. Wheairt X i IC is absent; 2 is 0; Mt i O; Rs Rn f>R and RN 'sre O{; andT Rk. R R'. 's and RK 'rc It hi a further mbodiment the compeand is a .socpnd as shown as fasmia 4 sond the sttmat doTnion, iermin X is CH; RN is absent; is O;>M S 0;~ Ro it, ad arc a0 OH; an R Rsn , RAY aud S ian T, it a AWhat xmbodinA , the coaound is a compaound as shown a kemmi' 4 and the andi dainidonn. WhmXin n t C, i" is C e' . " 0; N iS Cv a K sd i a CU; and 1< R R ' R. R'Y ad. R' am M\ 1.i a ntit tbo~diment t' compound W a Compund as show\ & bform R 4 and th, acaenda deriditons, wcuam X is CH; IQ" ': RbY.: 7 is 0; Ma is 0; d a O ; t and s Rt RC R : R a R : H o a hurter nmodtmen Hhe compmdis a cmpund as shnowm ax somu. 4 andn 4 suidat dtfton whran X is C X a A t; Zc is 0; Mis 0; RI K R4 Yi and R ar' . ;n R R a R1 are'>. "t inu r mbjnt, the comp&und is a o 'as ho I55Trn1d 4 4nd M he 4tendaat'eimun w X is C; R is &I; Z is n; M! is 0; Rs R aid RK ar H mdR~ R.K; R . and R . are t .In a nuither emnbodimemn thea compoundis a ncmpound as shown as iormuA 4 and t attendat dmun., wei n is CH; RO . absent; 2 i ;Ma 0 R is OH, ' n Rs RR R KU ' nR siu. I- h a fuither imboisem: the compoutndi is a cmpoinnd as shown a' tn'natda :4 and ikt adtlan.thdIuhdonr wiasaji X is 01H1; IC is ab; Z sE Q; M is 0; R4 aud K> sit: 01. and R>, R'* Rs. R.> RN R imd R$ Sn an: xH ton a t'e emoimert 5he SocenpQomel is enmpounda as shown as f nnulah 4 ad dt :tmndan defitsons, wherei. X is C01; R"? is *clasem:1. is 0; M A 0; R2 ad R 4 ams 01< and R > Rn Rt R' ' RR ' sad R'. are' H, i a father embdimenPtsA the cot~mpennd t~h is id asshowan~ as nmAa 4 and the attendant def~ initoshtaruin Xti :s C," is OH: .Z is O: MA is Q R~ RK and .R'S axe iK; and Rs.
R 4Ka R> aret in 1 a ti~gt mboaN 9mn is a ampnl4Sd as Ahown an rui 4 XandJ d drfriions vxerenXa CWr sbsent 2 iO;m S0; Ais Oi ad R A A 5 > R> A R r a y are .I a Pthret eubodnment hea -omtpound is a comnpoma as shown as formzda 4 and ha. aMiandaa denrons whoat is C R is OH; Zis 0; N is OfR, R A a k t tu'DH; adRt( RU. adC <'e n. i a tatirtboime. the nmpounda cimpad shea&. fod 4 and ha attndant dadhaions, wherin.XinC A" is CH; Z is O; M is 0;K. > P an. < are OH; ad A 1 Ra A 1 .RU and R aa H. a further emibodiment1 he csxompad is a cmpand as thown as faa 4 and te attendant defaiiins, wherein Ri "C; R* is OH Z s ; ORyggRMandR~r OH; ndFRRdR art!K t' an p r, :, A '. E- ~ is noter embedinwat a aittedivtaug ptniutd iY ni ian k.la1tncmnd Of tfimada 5: VPt R Ry Re RonoRn is a C and at Aprm as alkl 5ard Wetray R ~ i f! Ibeto ersnt iay r etrary afayyhraaly halid Z~ epresa s H UwN ofu J ; Z repesent OR od an Y repeengR or whe R ina5tso 5 amRp definiio n ,h 1 12k.. . In" a futt( emodmet etemandks cmlfA a ayin, astformadhy h5ia>nO.S OReat.ndN(t defrn rein sO n ad ,,,>i asn irersns siv il hwozx. ia/.heeoaakv sne winboimen t omptmd is a iopnd~Ui sa sh zts io{unala 5 and t aner ddiniion whearen~ RS sand R'> are ORt in a further ambdimnat L themio A; fok' 5adthe :aen' dnnnios: wheei 1 4 . A n R', are OU~ te sRtendLm definititsa, Whmein Y s C;'K" abnt Z is 0; M I' 0 Sa Ram' iXI nd &4 R 1, R R A R nt he om'd is a compound as sToas t tia S and the atean de3gpmnung where Y h> C R" is Vicent Z i 0; M is ; Rab and R ae O i and R Rs' Rn' R IR ad R' d ae il In anther ambodime O rminact vat an ymf ompound 6s an ananIdm arereintoedepenared r * Y' ' M , a sa RR, R, R's R R a ran a y ard .Qata haay la hea dk 'd NO<:SICfOR h1t.Rt cctaxebis RnnnAk i .QF5 epe tt ankor adhnd e~(dI~'im ' s~R3 n t ~a OR. in a I'mhe'r bmhomat, te compoted he a "omoun aN sho wt as frmaha 6 and the anecndant deiinitions whJ R~ti ThRs~ Ras R:s and R> are OHZ In a furtherr emoimm he c ommd is a comaponi as shown as foemrdean theN attenda decinitions wherein :s~ t K R':: R 'ad 5ar l i a fthettr emebodimenti the comound is a z emound as shown as sormut 6 and th mandat defmilo. wherm \ is CtDi, Rs R s and R( Nr *OH fi an 'a R . Ri, Rit R', Re and) RX. are II.ts a shyrber mboadimat the as'omos is a cmon nw as haoruruiaI6 and the artendat dfniins whrsin A. is C1^ IRa Rs. RC R' and R 7.are: 5N: and RNs R' e RsR and R . are Et I a snherta embodimenst the compound i5 a -ov poud as sownr aa remnkda athe ic e nwdan natin 004r0in i Qgh C A R C RU: R aM O; and RIX C, R sand Rt r totbod foe aQI . aig gbjsinui proaon, O fattwy me r xniay sdnl cgd conketinge e with a stiibcene chaone a, oron compound remnidaod b.y fosada 7P RR \R4n M i Oaent or ; Rb 1 ~ R R >, RIk and R> represent ad, alky 4 ary beteRary * ka hrad~~-Rky 4 h::)Ne Ny R ORwon&) or RarbT-yI vrarerts H or die two Reftor a. hond; R represent is aakyt omu as nand athe'. pSh wided that wtn n is 7 het sad R-arc O3%andR1,II.P>P>P'.S ~~th RiRs. ~ no;001~ i <h R i CH IZ ate N-a opy f R caR% R 4 oa>isrt 1 s
R
4 s otoatsxyt. Ir a tr strab&&d aun th pudi a ad~ pon as shown as Ionnda 7 nd dthaina deftionrs, wherein n isi UeI a fiurier strndimenr, the comuponda is a compound as shown as for a. '7 and the atentndelinitins, a$ein ois as ITn a rather ambodimtent. the coiranud is a comiand as shown as forana 7 and th aiandant defonknonasyheenfinas is tn a Lorther embodimnca the compound is a compond as shown as tornai 7 and the attedant definitions, wheratu M is 0. hn a furathe 'pmeduoned. th cot 3on is a Cofapamd ~as shown 'o tbrnda 7 and the.atrt3.daot defhitthns.whend R, is H. t fa other ambodihaen; te cenopouand .s a aecmpoaad as 5$w asItada4 *d hi**e ane t~ denW. XinNens N hnian 0 and the two Rk ina a bond, W a fier embtnet, th rnnpound is pound as hownas fud7 an I deatiend ant dd hbwin R ' in a amhe embodiniente ToQ. camprund is a as shown as banmula 7 and the attendam ttditians. whein a OH a thea empond shown as kruki 7 and the attriand defuatons. whein Rk.nd R&r OL Ina IthVhr at odiment the copa nd is a nompOndashown as bmnnia and the attendant d teftarn s rin RA Q and Rt' e OIL In a furher eanbndinent, the compoundl Isacomapond as snewn as fnno 7 and andad RR and W; twa Ohl i a further u denina, cnowo:. is a ompotnad. as shown as fan. 7 sadahe attendant denaong w>enn and R, ae CT. n a urnar embedenent the compoand s a ampoaa as shown al frmnia I and the attendant dtdan waintin a is 0; blis aben; R. is Its H; RO T. and RT are OH; and R 1. AK and R are H Ia a inter embodiment the ac4.vaing equopaat is a compnad as shownas mda 7 Asd the atendant dfundvonSswhoerne v L MI i 4 d R is HU 1 R is and Rvaa OF1 Ad RaK RR R4and It ane H la der hd t ae nvddn compound sa compound as shown as Mama 7 and thw srtt dfda wm ,is 1 M is O the two fann a bo5di R as OH;f R R and Rt'ar O and R R R and ME lre Other 'ytiav-aotdins eoanpcaund inch de compounds having a fnrnska nd Thaiti"'gnmp snsting to Amlas $4 setar~.th beto8SW R~~~~~~ Hk aly nffuingshtray Rl haogR "'"P' I-I, allky. oryl, lisiarm retsay R 9 R / R 1 ~eaegeeetesr r R R ha o gNO, R-, RM., NRbklaryrr In another embodimennte exemphbry shinn-a eata tompoud on lidaet O .Nr$4 $$ 2 i$$$ $ ON/48 00 at~ Pabtiicdot Naes 200)160W823; 2006f98 200210S278* 20$/142 dAusvirs <\4ica treher3>rin.o4 Vsed by otren tbcir endirety .n an emnar~ y US Pawn W, Spis" foehu 4 beke 't- :ne ksmbod *t n snigeadng~ comound is un seedcainandealg ooirndvc ct iaxnnu r 0810 Whereinw i\ i a nitrog.nuw oygetv o" uanKO nked a . ameAy OyCP0 or hteme-yTlit grup. The A m es thus derLdhd opinall4y hv Ieaving gmup deacteades adedann ag ncongased hrem, A is,, fualmrseuutdeha eton pantributing na~atB and C wa oit byamga, orqn eoB or C Ba rnars or thbd grop *ar othe B or C dingoa;nd a pdary a1pbboal hydasnor an xygts nitrogt, arbon, or snifrvyke t hshr apopey hup a pophoaphory gp or XnO1 mOnophsphe> Ihrough a phosp hdirtar r caa nrgra. or iiJraanbetitutd ghtsphoi45nte~rjordste ~aoaina diphosphat dauha rpoeirster or carxo nitrogen> or wdfitnsubtttd pyrophosphdese bri2. n one example, A is a Nustatedd ned aryl or beteCyelk up, an inked aryl or hteracycli grop living the &muida -(WV or an S-ihaked aryl or hezrooyvik loup naingha tha ; to> b n C WA hydrogen or ena of B or Cis a hogn atnto or thioi group and the other of B or C is hydrgen andL t i a primry lohol or hyne Nooliiloin proinod ex~ampjles of A sre sot itstb -a o.w heeaco hen }sT or tt a enioantithtmog aiety and Z is an tO'yi, ryihydonnz 0/ wihao Ztisan athk or aryh a ax NT{Z Zher B.i an aikyt or aryl. -or NiZ where Z? and Zte dpdeyu sk or ao 2 of en(A ichude Psive bdow ft 3mi 'N m N~MN ""WA Hi 1v All~ \ "'37 4 N V xma g y 1N ''4 iv' fm 4Xvl X i oAr ' 10d a da y a In otdn emodenent A is a hbstittdi4 n ootinarde nteng 6 e heni asubsttuted pyra' gro u(pii <hovo, or a subauted eOarboaniWidaao gropn (x abovenhero ida14.Addidty; bouth nd C mag h hdrogee or oneo of 3 (or C isa log mno r h iol grag ad the other of B or C iS oem ad D -i ai primary to!gup When, the 'zdkr of B r Ci a hydmgan mnhUm my he a hyd o en on gi goyp or ,,TIpn Relnpawue huh hpodi,ster,- Zor Cas hgs &W-s)ufn t phos ph -Ast bdg rr a. la d p h compund .onbuls nolr 14 MdOW Ox L2 wheminh or C "iky a y>hytho Oummahere\i flan" ay ar [di' oauso v>wher Zasrtn tkgd par ospHZi htd 2t awodypediy an alkym mt a azyE and in on. 1 C2C7 NOr mrt N yCohoNhC > Nisid G(Cnaoao artoier C ph0syprefer ad povide dipthaze 'oeafoft ra F is aherntcs rooa pao rdoi&dphphd.srps A amino/NHZ heT is? anadkyl or yl o Niwe n Zthdpneya alyl or ary. and teohrtoo n neaed ~ Ci ~Cg~ 14 ana c o t1hro an alky or ano CN4A hee and~ i& re dependntLy Zn ai or ayi oandri amideedey p H~k r Ow endgraide thanldefons H fuemn. Atht fBo7u die sm o tK tr dwy 1 17t i>ms7 W drv aod be bon j any pt a hsm i t ~ ~oody Cit 06$d CthCthe eitron cotiutn alt nA tb~zstecopudso i ivtonnltatteKa-ls dtzptbl oxydWysis fr'ra ahe ret otthe upod h inO pg noOLed P' :III ialsMity tilea Oa gz or z& ~OCC Thep , compoundibsb for *od h hr eri dsf time arbihlo aydai *r400 de o snce to hydfly4i breakdo Th0 sk,1Iw. ari141 ceuld envision mnarw e toncontributid n oiitenbta woud te eted to servc his. stabilhing tfaAion. Nonlizahing n o Mpies of suitable detn 1 ntbutin: tr edes ay met d hy, Odeacthyl amino, Ne2. ydroxylC~eo3 aryl ad alkyi groups. Pefrxblv a decivaoribming msar)ty du a metyt hh Owe&yt amino group.a the mt prefexad embodiment the dechescontrbuing moist'is amethyl group. Tc dsof vwfidar I e sfubo i flg fenn a Un iha m oa f salt. he term phicmaceutkaly aceptabieasaitQ is tended to apply ao neatode sales aerived 2om inorganic or organic achds and includes, for eximple. salts da OOved~ fro feihtc 1gse ydigaeblric..s 2drk phosphbonr ntngeic. tiit d94tCaogiaic Snade glwoni tteitanafiaapthaslorin dN'baC MAlo provided are compad oh fe Ials I 4 esat arc de t ta iske ICZ ttb tuteh i h i ec ific The bhiologid aai y of the oopounds oftmmlas i 14 can be enaned by aoVnte n i Ot drug konai. Such.pro-&u can have lanve Lipophinoisyntiuve (0 the ifCynlVeteCd compenOdOand this can4- rest't in ,4bA en ancd m basa. pam.Clsaity One particsdad:.xseful Loom of proednrg i an earserivative.a utility relies anon the astion of oneor increof thre rqinitoan maoslu~s ipses to catanysethes hydvlrssys of ester groups. todesshoa cti wve compound at or nea aast faemI one foonmh r p augone or more hy'drxody ' .upinh cornpound can bena'y'teds taakan aCswate derives Pnrtug forms of a 5phosphat western de'av of tompunnds of Xfinls: 14 u Can aso be incaen "s 'tay be p erdady uefulain dce the sak naere of the $ pihasosat miay bioit its abiliy to crsmess a za embrasa Conv entnd sat a phosphaeo drivativc can be conerted to an asbharged ioxvnysmsdhyilester dei vative. Thseri ay of sect a prco-dug redies upon the. ction of one or tuore of the deqijceus inmehalpases to tlyt( the hydu yais of aSter gass teasWIig aO mhAke of formedehyd 'And5 N4 c-ontpandeofthe preen invention at. a nssar sea sze :of action. SpeA& ce:amplesof the utility oEl and gesal metod for maigsuharxm.tese r &agfans o phsphry te c a nthyie dedaeae have been described an t al 119$;ang &t, a $98%M e~t at. 1992; trupa at uP99 in~~ ~ ~ mumra A0 Ioe anmoigs, hindlog g-natty! ADPIribom and0 ef ldeen nlg thereot eencdzary 0 ty P oe ndf p ?4ati tpb iam No& 200)4003944; 4r.. 89%zand 200K0%6 betdetiusuAes if wh> are horeby insc2. 4rporaved byy b an exmphsy embO~at sitai-aevatnng zompotesk may be ax& OecayteD$V ta aoz lhavingt zany offormuha $4 S baow n ne emzo.ixmnta a. izi mtivaeig compound is OnK acetybADPsrabose anmlog noropound of fonada 5 A, A1 adczed fcin R C whe> R is a ertHd from halen, opionaly subsiad alkyK aaiand arti Oil \W NR N ani d whhk and A arm ach optionallyv subitutmd al andkyl~ or a( gtonp B is shkend fronm OH Nta NHL 4 I and halcn wheWt. isi an optionally subaited .at ra~vi or andl gwupr i;tia siated fien ~ 01 N''2hloe an SKN where RN i ~An p y ld Akyak or ryI grom X Y d frm and ogen with h pois "h when on Xi andl Y is hymy ralg w h othr is hydrwgw d is art iodonoid is .. e.e AOn. h y A..Q Hnono ~ Now" IAK.dt'~u V z and (OQ 4cw hmis an optionally snbstitiued <dit, arici or sryi~ gap; and NV OH > or N, witi dhe proviso fial whena W OH. thsa A is CR wha R is as deUinkd shovo; or a amorir tienor a pharmaceutihity asPetal s ainedor an v.stor rhasrof; or a a tainemborAsdabe Bs is NRTR4 andDr Q is NTIIR5 n P ankir i 5 a C7,4 nahAkyl.
r~yhre and fhuwnt ho anthe etnbdmtnvhe 2 is SQ "Ur OQ, )Q it: C&.s li phanyi b~ut bodnplary embodiment, 2 is 5L orwhn a 5the thnV BP is O I t Wrebly t Z s OF, .I or meAyttUo, epmuy OH. eV ian "Ain Y O n I , ii. nd A .: CR w3er A elns (W Ialogn. rt h frtn W other s mdinmnN u is uabmi sodA is n oto ra t na raniend w. noMM A a anudtg assodid tnA ~ 601. d wanS AZ . Z 7nd Rn oat. d foopomdnaf lottH or(MiOTre wlst Ct td'r tyd' i hon faen C02U r a co'pondang nAt ku Cm(0%RONH fN4 NHRh fr CMe and O is 4hznsa NtN~o NEON 1 gNNi a .rti'ekr ' pluarotivA incxepabk i sot or an ser tereo cc In cet tn embodimeants L' i C.ON * anod Ci is NN~l In other embodiment. E- a CONH s Gi N s (15 OH4 m, a5 It mt~h pref&abb W)h 2 as O5> 5 or me~Thybl . pciWyO 10 'S dideo1 i44-hysimxpyo3dapyrimidinly E) mitDriic (1}C"mn~ ydoyyrll; joniial ,4ddoy 4m r Da4) TA n miPy 1-v4rihia I r4hrdncp1nd.4 (S~' n .dViyd<ypymnrgar] ydon yN ) A*X4 'de ~',J 4,T ~ ''1 riI y4 ! SI- C-Sdihvdyox)44 nibydmxypym [3p ]uaidi-x1,4iing44mno5 Ddrboyib $~~J. NehytNo Aeto DS) ddwaym04&dsypya4[44paii4yR4ie (I} IC45aninogeya.xyamok4C ipyvHeidiylkiAdidee&} 4 oudwc -dir wo I ( 2 iesmo -bydhok'ypym,,olo dprndnypsiexa '4a- -4 y D (i$Vkt CS34miin7 .~ caxxaldf4tteyh4-ddeoyi ~4d WasoD-d1 i V N SC (32 nd bxa d yry4..d...4..nino.ibit Q4nalg toop unda of tfannuh 7 a 'I$ iti tdrats and phewna.&ically aWaapt4Ylk sah *S~kS.
'N
&h bio{ogicalt avaiality of a aompotndi fu~nrtoele{ 5) ronmla Q (4 nanced1 by conversion into a pro dra kaa ed( a pOdr.geao havv improved pophilicity ralatixv to ithemoundoa ofionuda (15) or fAuia 6 of and a a i. eao to nreed m brne pensabilig One p Iti y u 4 ~r at'f a ptess a Of uervaivets utility relies upos the action t o r morotk oe biq ious intenytar topaaos to catalysedhe hydwlyse of these eter gtrrops), to release the comprout of Wk"I5) ar zoa 1gt or iarits sitaine ti6 in one tarnt of a prodnva. on re or af tWe hydr . pIn a cotmod of faa r S a la (16) ea be WvDljtedto mhk i n(extngle a 5 bt4mtC or a 2ra m hut mi! dOwlvative. Prodg h-on ns of 5--phosphate ester deiaitK~ of a mpaoa oftformula ii5) or t uda QS) t aso Ito tade sd may h patdi hady . ,iahe the agitade a nat . he. 592*sal iifg um' ability to ezose cola membr-snes.( Caentlyku a 5.
pphgW dv e nt be convetei to an chsrao bis~acylo ymeihi) ester dJimeli. luteliliy of sudb a pradrag roies upon the action of oe or more of the nbteaomt 11=e0i1r ipases to ctalys the hydrOIyds of thse este groap(V kdadag a reaioere ofn eyd and ah compondx t o: Imme i) or fmonmnla () at or near it site at aion, ,nt ex phay elubcdinau ons at AAIDPR or3A.DPR tagare to hame nereased std ity tiara esetas 1 a dtrough the usO WOf w hOwn. sbtst Not aster oxygen tomls that are suine 0 esteasa ataeik 4 he estvehue oxygen tOems it ADPR Wd TMADPR would We atwkwen to he te ete onyon 1itlit the acetate gonp mid to A am tr n"yg"n b en's' twxo Phmhan an:'A "dC UM 43 bo a la known inth re n unation ofeither or bot of these ester oxygeaoms wadutY a NH. or ad S onud be expected to 'ovhde a AAPRordAADXiPR n-doe tsh-r s b llfore stable due to nceaed resistance estoraae actan uine emboanaete tue invanoni is direted to nd ogo 3 -O -SY dase or.S.O-acoAtDhose exhiidag increased stabithy in cells. The preferred antlit comprise a 2a NHer a S instead of the acetyl eser oxygea or the oxoygna 'tn two phosphamsl atonut 11he01(St jareferred :substtuttis......(5pla411med a the soot vi eater oxyge is particuhuprV eferraT otherpeted wdiodnts both (ithnoster asyeet and dhe oxygen between the two hsphorus atons ar n 5 dopk-ndet n abatd with a GCN, a Nt as S. We ~ ~ ~ ~ S tSMU yyvi f 0im 6e.~Ir ittidih tiv: atingi' cymoun. are Ve Tnd CntheZ~ capende TV in obmahoed f ionioob.igmn~kkiih or d o one ernoocodienmehdvss for aaig a sittain pntvra copist stng aawninmg copoud that i a Mdbene ordcone compound otf fenna 234 R I JRR 23 heIdednti~ec aocclxrA hd amrencmpace-faima23mdtm R. R , R , c. an d Wreprosent 3 aikyt ar a hrA aagiviN iat eeroarmlvJ halide. NO'\I SR N(Rt or carboxy* R4 represoatc .1, Mkyi, r ary e otyi. amk4 -SOM mnclhad x4YgN acchadd glcofima gycpranoA.ygin -uoosyl. tor~ ghe*rni >f represent 0 NR e A eysnt bivalen> aky. atkcayg alkyoyt oridlo sttifnoaarnid#OSS, de AgThT siyvrnivo aiylsotinde.hydi igarrmn orhy anrup.n n4i is bi abiy aa fthoerodimecnt themethods coampws a cond" of fanla 20 an-id the attenda't doditins, 't ein a Ci.t a. fkuThea entodinent. th meothod' comrise a pn twen.l 23 and Vleectint dearno whomin n i ithhc dpfio don. whertin AsI i: dh'y( In a fitawl Qrdh$nhamn thah m campcond af itrmala 23 ad the eaenat dennsimu a wvheein A-B is Cig htfl)O(Mi). jo a tindhe' tnhodimet the mat d mzupdie a com'poimse: forxmda 23 ad tr atadaad deiinidtos wbui M is 0. In a .ttrherabodiment he an4m-daaesa s. etsnge'd otVznntdo23 and thterdat dvennaien 'ahareva R..
RsRpF Rs Rn RU,. RU M R' and R's ate H. n airher ewixxiinent, thew mediod yn- m Uf U 3 and theo atenkdant dnitioni wherein R" Ka R CHe n Iunhor Nmbodimntrh m d c Ycpu of femmUa 23 and the atedn deiiioslheenR Rfl R Ym R we OR in a fute moet h MOas u a pm kfAoa 3ami the atte dam denniton WhereinRR RU andR are OR~ 9nafrhraidmr 'iKetoscopa 'NAA onad a oruula 23 ad the ~taadant dtfiitim, ihetan RC is Ri R aod R are YH. in a dfinbkeo whehin Rnandn ni caryr R1 oi ad l and f.$ia O HIn a taa lutrer emibtdoncat, the tods c a compmmd of fua 23 and Oth akmianm denitida Wher5 MV ; R, P n W Q 1Dp AucndR7,e an; i. A; BDCH In afurthe tatdia.9e iemeth .. od smpda C aseparea ennem.. ad h itendantt deftikt whreWA; arind R Rs R2 an RA R RUN P. R'Y mi R e are (tisra dThene tn a tenbe embodhen>t the metluxh: teae a i n the attendan dN-d1 m Asn i 'A and RW it Rt I, Ra R t. l.VR Ro t R' >are to ( OO n aprte eomoent the methods comprise a cmnde of formula 23 and the attendat de(ntn, whe n, Rs Q; AO is andy! R R an 1.54O; and QQ R nRndR s H R3A'AGR R~~~~~b an Rar OMreOS Hormartn aate ebdnet ehods compn SnseW af Romevi of amuoHla V and ohe ad lan deiios. i wrn W isvq; A0 sF i (MVR Ri mnot R R' R Qd UO am H; (piRno I ah teu emix diumm,~ uh me'vds comprit a tcormoun of forida txe eante aneiantC ds wrniA is h; M is 0 R Rs Rb id Rn compond e fumiu .t ai ahe ~attnt de iaitni. whereim a is 1: A4 >s emnl M 4 pentaydroxchakew ) 01n1 mA ;a 9. mbI d ien 1 ehd tomri, foun arie Mmun mew the m:zd detsan hr a 6fu-B iaby: R: ard R't e OtRi Ranmiw WDClU) o d #kR is >Ctan R i : M R' & a&nd&. tt N (re H (rhanti Rn sfrhUr embdimUen' te meihods anpi ta etahcnptun :Lf frtmta 'r nd~re th ud <;innmuuks, where a is W iD Q.ciide, iR nd R Rt R 4 R iR'en 1ri6 arrndareC c(de scyrhap.n) a4 a8 frr emoimt thei Ctreito~ cmrienacmpudo f mpr k2A and~ tA Aucudan3 dei~n.wk-n"(NO~AISi CIQeCMvCr I~ RRRU,:n ind R R R nd RSV F ae (NDJGAV at an' k: t.th Wds for cdivaig air in proti ri w in et vating. cmApoind vtsisa onst pound ofrmana 2'4 Rl R ~ ' R 24 R- Pn uv F, ~ v mdR pv'l"'" %N ~ R~o R4a iu, a~ 24 s. szno Me amdrrt'. iMv axXens : w wyaRR R4 and Weepenn awwo6004y.loumR n nanlys Leenei arAk ttkguaryl hetroaralk Vihahder.NOb SR. N(R> aot'rba i1 R 'pirsents ; avIry rsrvt 1 y afky -An 24 en to scchanide Sresenets HR 0 NW or. N rep sentse OR v > ar Vreprvents CR or N.an iv afizthertgmboditnear the nathds comrprisa a. cpoand of .imnda 24 andth attenaient deitiosg temin Xand Varcs btxW{ (2 l a fwthvr cns~xkidnenitNha sntthxi te pi ea compnIX aC of fo nl 24 and st amndat d ttis on w hr ein M is 0> *fn a cdher ocokhereet. use ne cvn 1opds.-'t a 'oi'poi" of"' fona2 ancd the aedant dtaionics. titi MI se In a hu embdn ktnt, the> metod campd>s. asomoun of fnmaa 24 and tho atendans deijaitionsx whoranx 2 is 0. In a further insbadienctt e hascmpdc a campocsn a Assad '5 arc tue tndnt destdcss. Whomsh IC attendant defnnsd heroin R'5 as Oi n a (urther einbadn nt 'he mtods conprise a conmpaurd of funmda 2:4 and the at uandatdetntades, e s It an alkoxyeaarbony1 In aS 1tadr ercrtuenent. the methods compdSecimpound of tsoranda 24 and the amdn 49 OH d'efations. wherein Rt:Ias o a a.fidther rmbdanat, thw e h as npiotase a copound of fodaiu 24 a d the attendant d etnons, wh R' Rs R 1, RInR ad R ate I autter embsad men t ha e ntlos onpise a xonpaund of nmua 24 andthe awwndant dnticna treim . A ad 1 I" Ott h a frten embodeirSrt the methods compuse a compound of fibnla 24 and the atteant deinian hena :. RU. R and K are OH tfmher enivhnet the methods ''"'dse umpa, L a r 2 < i the 24endan:aa i '.d" t\n R aR and R' arc O aIn a ta h txhnbodim . the neians compris a compound o vna24 and the attendyat dela~os, wheretR R R ' R R and R" are OiIk in a t ter embodat("nent, TO Sitea empt C am poundd lanu 24 WAd tihe otenwane deittoas. weed . andi aCe 0 C; and Ot5 Rn MRR .R R R24ud asoe avanoneYUaftdher tmbtodisent. the mxetW comxprise a c'pund df n falmda 24 and the awstmi t o an wh ad: X and Y nse (T'i :M Ws nd O;WRis 1H; 0R id R1 ate. Toan V ' SA R OOM R art Hi tnadmg~'ni. ha a fehan'r'ebderm'9nigh ettad 'ompran a compot1ne of orCH; 2 in e and O ; ' in a W a daataea in tAtuth-r mb x'dnt en pound kLf ttmaitla 2 nd the attendant dtefaxtans. whercin>X and >a re'tU Nlisa i~ 2: ad R "is OH;&RsRitad R'; ame OH; nd R b R ';R and R's me (eptkateehtn). :5. fArthaerenibodimnt the mtethcods nmise a erapeaad of :nzn 24 and the attendant deadon whemin > and >7 are C(l+" l Zav and 5)40;1W is OH; R: R<e RIt I and Ru:. axe OH- and Ra. R. RU and R' ar" N (galrn'tee in faMther eikdxeat he 4 u't )ods tp "4rise a ttepst of kat 5m 24 andI the atedant definitions. hamin X san H Tate RIM 3242and t R"is f ; 5 .Ls R'R% R',K 4 R and Rare. 1 ad Rj., ReI. and Hi.ate H ~pateteden galnate). In other cnmboimetcU. muthe s for aedvatinita sinul protein Qianpriae usinian actnvatng temp~ournd that ~isa sofi~ava.nn compounxd of fenniaa 25: an R1 Ry% 3' bAsina, nde R'ndtiy soe awcsh ocMuntren KRn e;R 1k R1kR ~.1 R\ .. eand R"' repomnsitH amyt aryK frryle. adnkyit aikgAryK etaoardl adx NQ, RN OQ~ N(Bege :4a&boxyi R. Alkar&sU Morstpvy, 'amy'TSOA oanoffharida. M r~CKepmdnal\g NR ory ;~y L o o X ieetaCR or N; and Y rosnts CR or N To another omba'im'. mepdsd fos aivaing a sirykinproteiu romprise a'ng an rodadn campsd dai a tvcn cmpound of fo ada2 6 R < R' 2 itsM 26 yhd S&,VAR N(R) My\ 'k R apesnts It y r benoary taik>{ -80}dL xoenosaechadde, oli oNaccihuide, VCy4ofurlnigycipyrnWSYt glacQarooyy r guaan t raja alsmr k aa iadeM SRs OR, N(Ro l ao nitr amon h omeos 26 and th et 0. N Ri ii'n an de .. 'iky, Wreid I s I., a Kt~ dm o ieri& the 62.~d coillNfRezi dIt thore 1o1i00 n C tflehe a Di e0xin a 26 a tahed defiti~p tons, en isO tn .a tirtermhtsnrh medihods" comris naSa >oond of "mu nd ilhe aedt atons winM iina vn a r boimtn a h d Ce a copa of femaa 26 and the w nR"s H, tu athet emoiment, tbca tthod crompus anth ompoud~ oth Aua 26 an he fln26a d tdinitionR . itatite emtwdimesi thhe meod R-mprise a aiond o ttda e anthe of anda 26 and idom wten R afR Ra RaeiR R I R Q ad It Iar' R hiat the methods a mpe offnm amda attandtth A dadniti, os, w hee 11o a ad R3 jr t in authei emoiet, flWT atd ionp'26 anyond of wench 26 am! the rtiint deisr, Whern
R
4 . art R'> nd RX T a ttha in alnit modm the mdboddt comprieatio: au comtmd e ofJ 'ftrtia 6d the a ttendan deinti, whpc in Rar He R an Rfltve OH.i ~in ai nther emodme . otnraeoznohad. compr ola 2ompond ofa etnatau amnni te nnd dSti.n .w Rs R' and R4 am a trebOritna rb n m the methods canroieacmo ffna 26 and the attanddnu dennitionn, wherein it, R.xk~as RAl. anda Rhtare OR hlnanv iurth ehdt mentp heamethodntcomprise atcompound of'nmodt rtand the tdan tadeintRons, whrendR RT.dR are OH.ltafru hi s nhncna mboet, ahemeo omis a noy 26 and rni 26 mh ndant el, hein ad .R; a in ar ma torhemb t the method coposet r ompomdof onl6adthe attendantt % definitions,~k~ 3 wherev Rs4X a Re an it ar M n ath enebodirnent, the methods omnpiis: a oonpaund tf 'urnmda 26 and the atneadant &deiaina. wheb atd , It :Re.ad .R an: OHt in a kurtbr embodimvent, dte mesthtds aops aeompountd of fborreKl 26 and ihn atirmdart definitious. wherein Rs. R';. and Rt> arc O~:, in a ilf otembrtodimem, thes~ meerod ner a comoud f anul 2 6 :md1 he aUendcUn def&itiona, wh ohe rd and RIf are cy F h at > crodm:tatemeuda p2 dfno w wher& in Rx Q. 0hm " .. &ud, R. ax Ore Li in a further demb-denienh eetd m a oMPN d offRO A 2 d the attendant de'initions. wisni uR n and are OK n a furhe ensbodinende iuehods cmprise a compOnnd af In=a 26 and the attndan t i i OIL In a father emibudhaet t: methd)0 comptee a compound ot wnna -d attenat daw ntins harrrin dlKand H'. are Oi in a nrthetembodim~ent the methods comepnse a omapound of formuur26 and th4'edn eiiiosween n r OH'I ai furterembdnent theetbads comprise a annad of atnmie .26 and th alt ndata defuns, wherein R R 4 M an R are Ott In a futther enbodi net, the mthtods compise a compounct ot' fenaua 26 and the attendant ataitious. wherein Rda i O. la father embdn0eJ, the methods porptnan a cmpsd of anda 26 and the atdadenifhio>, herni R 0 N! is ndtatl & a hr!, emR"dnre theio compuse a comndrl of Thrmla 26 and theataeat deftahons. wherenn Rt
W
4 , ad ; On H n b 1~ais xfC .t~ttS 'qxon-'l i W nnad 2 and the 1,andad dhiiona when R R and R> e1K i > athe embodeknet~hi n'eiodNs na 5eh cWomOned3 (4 tfltmn 26 ad the attedaa decin W onbereint C UZis O;M Ni 0' and .. Rs R ; , ot e a nd am e attend an ee erien' a des Th idiiscpu s. K> amnd Sr~e OH; andO RbI R~ R> i and R.> am H Oh"'s a ithr isishodiment, the nustork eomnprke a eoampouind of uhra 26 and the aeda efa nn whsed.Xi a CR;~ ~ ~ ~ R' n:o i 4 s0 tIt 2 <md YU4 'o ($NU; and R-, i>~eI (t~345peataiydroxytvane) La a further enodher.t. the methods comprise a ompound off fArfrida 26 and the atendant deinition herein X is C; N; s R&> R -. > and K> are Ot and R s RY N Ad arehtterli) a flrther embodient, dhe methods oprise a axmpnd at Armaah 26 and the ns;enda dfinitons wh ren X is 4O; Z is 0; M i 0;L RKaM R>are OH;and K.. R, K.. an@ f4(3r 34 H 4VtfarahydrS~v~atc.ine a fhirmen kntbodAnntinh he inches cornet a cmpognd of Amnda 26 ad he atendMndetiakionsherein is OO;Z.is O; M. n0; Ry ' ', AR. and R am" CAL .ndj R R and R> asH (quretia4 In -ti Adh embodimetthe nathod opanre a nsmpamd of lian26 and the Mendant i ln eX 7 2c4 O d. OP R -. Iad R4, P are OHt; n It Rt, and tas R'p and R are Rl In a tflte embdment s. ehdsmr a "~nS(t~t~C oflpoua n ofraonda 26 and the attend dimion whm X is COH; Q i ; M is ;it) 0; and on R, RI Ri, R an RN a ft tmbodit the m"Ithod' cne a ncmpund ohoa 26 and the attendant defins wherein X is CH; 2. is 0; Ms R, a r 11 OH :and Rxi W Rn R.'. aN h mbdimn tmebd np a cipound of t(monL 35 and the attendant de~~S~fniyen enai X is c'1; 7 in* C; M is t R;. R .. and R > are Oh; and R~% 1L C IR I R .T and C are t iu t k rthr niiahdimemF demthuds~j LP cangd a tona-und of formu ia 26 anfd the nndanti iions, wheNm X in CO, Z i C) M N C: S R ad RZ War) O1H; aned Ri Ris Rt R< R' i.m d R. aren 11 tIn $arr't w uwo unt dra methotds c ise compmnid of Qrmua 24 and the at = t dirtins, wheriX h CH; M Z i ; M is 0; T6 and R' amC OHI and i R Ra RC R'o R and R0 aQe H, 'n n embodint, the methodA compnse a compared o fora " n h endamI deftion:ri whexemn Xis COd i.. 0; M it O; RL. R4 R7 and R U are 0OH; and Re. R. RC R 1 anid 's are H, i afuther emoimem. the miite tds l~ copi ear mosd o ftomnula 2. and dhe attendant definnna wherem .X it CO: 2 s C; N is: 0; R 3 R and an H: and R. aR R'-. R and Rn' are H. In a fuhe mbdimena. the compn (alstnpo of0n4 26 h a ttemsl. NNMimiions, nIn Xm V..;./ is CL Mg is (: I is OHl O ne St, .. R 11 R' R R'a i R're R Tn aW,,-_ mbodmet e made compde. a compound of Vnmwa 26 and he atenamn tit intin w! ini is 0: M 0 and RaiO-;and:R1 a R'C a i '-are H in a rther ediment, the methods compme a compowd f mt 26 an h atltnn defhiidans, wherein X is- Ci; e ja C; M is 0; R 2 anid t are OH; and R R: R' R k F 1 aind Ro are . in a ra . aembe-dinim, the mthode comprae a compund f frmuk 6 anidW the atannt detimitionv whe'rein.X' it COH:; 2 it 0: M it 0; P"; av W and- a hr R%. R4 k' and R Zi 01e OH:t and. RRa R' R's and C's ar 1. Ia afuhe edimem, the mnhodx corNw e it crtmpAund A Inna 26 and dtesds Adontions, whrin X is- O A i ; M"~ C- it C/HI rdd1 Redi. K R-4 R- arnd >ae h na tnner awhedenen aita de a pond ia nadi'wn- t end.' diit'a dei when is C e T RS i W; and .O n V, Za (je R i i a IC Idvahi a U hi utretubodi. tha WE= aOmpVSa Ofmared fo m e and phttntda on-h i Q R'C i ' Or4 odeR R Ad 4 ta 0Z aid R t.C.,CYand IamntH ia. a teai di dire metdads pSe acompan d of' Panna 26 and Wa adn dlfeaionmh, *rair X is t Z i Ms 0R R RI iad e Oflud R. 5 fU. dR k anthe embodenntnahid* for :autating a sittin protein ncompuse utgn acvad.ng monponnd that I an rwfavn cnmpoand of ftnah 7: RR whYereindepenadentlvfr (ah oc nnZcr ooK I K K>. a+ 2 4 and Al reprst inlkx. nai uiy tetea;yl atalkyt adkaryi hetax lkvhalie NCX SR OR NoA 7mrb R "'presena N alkvt ary Ireteryv araeWyi; ISO meionoacehnde *naosanheode to vyofuriAnsy2 glyopyrnnos:y ghly er Mod InMa thea e-ntf knda pr a d f and.e 'Yendantenni:ns ohrduYi R N.wene a re mednnthmehacmpea n 'nu them' ethods cigd. a wonspnund ftfnmad27 and th den defiana warren A iSa 0In an fh hrY mb.Anne .h method comp se amond. of Paunoula 27 and the attendain defiyghions, whanera.Nt is 0. ina a fetther nnmbodiment the mnethoda copise a nomapound of fau21 and the enradefini , r an R> $TC OH. hn a nutter emhodimnia the methods comprise a comrpontd of iran 27 and the attndant efhanag wheri R ' aa7 ae' Ja fathethinnt ands company a componidat formula 27 and th unetyhnt dfnwusWtMax Y in CR Z is 0;.is O R d R> ala Q i and R R. R 4 , RQ R. and arep! a tnhr em odiant hodtoda compiase am paoad of ~ ~ ~ ~ ~ ~ C M& 27 0;, M iq O'H C).'4 RN" wHna nd th att34dan, W jon WSaton 'i mo i A .
4 and andhar aawtunbo metadas Air na aiaa cenpuStn an aerXag compound than anrtzcya nidi cmpna anlrbmdaa 23 wheteigudepndenu took;c oncoyrmen Reha~sin, Rnd Raodo adt yunkvT R IL Mk- , LNL) N.., .R=%=r digotcdiaid. gnanaEbryo a oglycopyeanosylg i0Onosy Eoar lnde>and A tepresem an an selcted famn tono Lckwing C r ou ILI a £urther iment thodscompdsea cam trpounrdonland and the attendant da:Nfn"ns whereQed is Cf. 1 a nirear embondimmglthe meothods caomprise a sompound af txmuis 28 and T ;ttdanz dentni anwrci, R 3 ,ad Rears OK tn a Uxther armbodimmen th m rnhds cempnse a cmpound af tantaa 25i andi ast anendant ddei aa whwereua 7Re,% AR~ R and R> Sx OH. na finbihgendoam thndos mps aNl compa'nadl of fotnad 2i aad ithe adnd~am ti endos, wbhirezir N R I nRa a atrther mbodime a nt h hds co mprit aaos~o at conniaund o Vmnt 25 sod te all ndat defusnidmng wherei A4$d R.:l; Ri R and Narc OW and Rh as iKR R R 24 and R are I in iWAnThcr mn xpdienr t e v seb anapne a compound of fanada 28 and the andant dfnies wheran. N is C R...A X R and .R' lH; and ROS&R , Ra d Re 11 Me teds for tWvating a aoin in mtay &o sopdse ;ia a chakon. or flavone md represend by fonua.29 29 Ra., Radependendy fo and oeandc My2,,I is irkn oO A Rs RItd iA * RriM wfcatepres I - 6 e lowyl anhtrn dn aakyL ailkayt hetoroaraikyi ,aid .tSi dR orcahoy A< rtp 09 s an or tho two hitancs o? ! iorm a bond; R rresnnts 3< ab yt eteroartI waWy1 .$T monsadecadxa. Sa ardeitoranosy4b pitaner y glnronr ne an by feintnd 29 and the attnn definitions, herein ai i 0. in a £ttn nhtodiment thW mtd comrpitaaadaig oompounrd represented by innmula 29 and tho anant dannisons arherona is in a itrdaer enbodiment, the mednodis copr an activaing campomnd represored by farnnta 29 and te attenoant dtntiona wherin .M irsasent in a fithter etabodent, the methods oee riso an actvuag comparund gr esentod by ftnmnda 29 and thetanat ddeihitiona, wheein Mv is 0 in a ifither erebodirnent the meothodsi comprise an actatadn compoulnd repesa.ted by ibnnuia 29 and the attendant definit3nvyhy 4 tt~ 4 R. . s ie hga itar e ndpdncrx U th *hed ogA e 5 cie om am .rephre n ntal2 T. the pxena n dn titn±p M<-,iA .ieland Ole two R.foI a bVnd v fonnml25 4a d tha attendant disJdnn, w R 1 1i Itin a fivdt embniian't tan h c nz sa ing fom n represented by fnnza29 nha"' ht an~niatn whera Rs is (Md in as ser ernbdimni, at ehu cmda enyag *empondm? rapresanied by fornmda 29 and the atendant dniinints wherein Rb ad am klL h a fAther ambdilmen m thei methods cmpns"' a vt prsnearl d by vda29 2thnd inant d n w rinia R n r aN n~~a -antiv -&U t2 - an nnacl a Aather e Wxde hedento.pnip se an acd n a u epa Ar da :i9 and the attendat{idfnawharain t and m era OH. in a Anther nne dmUOn the mtAhds tchaS contacti n e it an aeinsti ng compnsd ipmtented by nana 25 and she attendant dtni iu" we a , Arhen' nnd~imnzt the niets d n-opsm an act ('jf g *niea eknwtS*b1 femmia 29 and the attenat denions. wherein I in 1 N! is absnt Ra i 1W in H To nwkads r4atupd. an actiadh s cotapondt eapteented by frsumada 29 and Sw iedard d wefn i natin is A. N s die tw Ritn ad; A R and ., ( OH .. d R R ',mdi., aeD Ott.1 2"'91 Ia niher ePxbdent u h se ad cnque: a Inun d rptstnted by Manna 4z 29 and the atendkat definitions hernn 9 0 l a bater ~AnkhAicnt. th' Sdhes~t comnpas&. a comnpaund repreantd by nmuala 29 andte atiendantdeifhii eaSw"crm a a In h a turtbar emnbcdhnnthe mntethoanmpsrse a compound rpsented ry formula 29 and the attendant deftitiors wherein Mi in absent in a furtheenabadineent the attizds comPrine a camOu nd represent by emin~~ 29ctd the taiant defin~s. teniM ifO (Itn a fther ambodini the methade :COmptneZ a comapound represented by ifatniula 29 and de attendant defetion.
3 er is H. In a ther embdiemeni the meThods comipane a ernaenned s asented by ifren M29 and the sttennt dfhanarinrdt M a 0 and th two Re an a boan ha nther embdinent. the minds ccmwpnsn a eotapmnd repnted by f'nnhk9 and the attendant dfnextionswhemin Ra 1 s in a a iidnr riefim tL wh~1dn. is~x Oli in afeno amoimn th ehd copm copon op sened by formatda 29 andi dei atten dennen wAmink~ R a tan R re OlR. Ut a rather eodimen, themhd omrseaiopnd rprented by ornar 2t) and the attednt ddnition, whomin R, R4 R S, an RSe OHn. .rn a ute cmawydimotthe etau Cyj a COremlepnd bpR.'ne %y brimdat. 2.9 arid the .tteada M RiniSt Qii a R', and.d R(Q aem O, U a farthr ditned tU xnethsdt f0r Geeditta tie t spm Of a tuhryOti nai Comnprise et'nta the ced with aicopod represcete by emulfa 29t ad the aztendnt aloiton, w4; no I: M m abset; R. s d R. i it; kn Rntl ir' Ht WTd R rmpo v aesed Ay ofbwt' a and :K dnt d !NVI0', oWhd a s I1 b ts f'i 4t s, iR id R are Q; mulR R R and R re ASa in Sfhrther imb intn, tihe met hds cmpda a o enad rptr ed by fnmt 29 tod ax i R t x 2o R; AR N S y 28eachan g atano 'yoyan immK m R Araploents msdalky a is 10 , llr R IInd Rrrytercycle or aawl P1aky Ak en1k, anw rere ao OR< Tebpreset $;kylv ryheterary arnlkyi. *SO:t monosacvlaidek oigosacchadd4e glytontanisyl. gyeopyraosyt hI4turonoSYit of g'~iugoe ANt Qaod O) repressi CRs or NK and a i 03 or 3 Ra represernss smalmy Rait RN RV 0n R igosccde, gkyauansyt lycprany glcrnsr gl ueuriv):lde; iat (korr $tRy Wnd RgrepreWent H ary or ey n N N Ra oN N C ~viV nre~mC R or\ whRp ,,en,1q indednl fror iath Sit.rrnR T? roplavyQst H, oye M, h ar y', R R4 R 37 R. R R' R R < RU 'nd R ritYents H xiLog NO 4 Sf SR R. epeet H~ aky ary. heeyk araKt 4es(*h{d Aigo:zr s ent edi ) A4eiyn'& andd a t 1fnadd a$5 mk dU A R 3 k37 PxR~ RejRtRR R> and K> present I haca NO, SN 8R O>R OR, NRR . kflt aryie sadoy 4Z R epse . H ergthetemaryle ara-kyl c-&n) monaacharide, W1 raspresents HI alkyi~atyI.hekrykral aclS L -ketmanovaldde, ipgoseccade, glycofhnnosy, lycopmnyide toir gugnd A-i apr' esNts eeehyeaid sultaamid ttntxalkyi, 4 ee alkyA aine a kyisuffide< hydmxyamine,e Iodgadmet R RR R O R4 63 whemin. 1:eandi" a te earrhalog$ecratTRsSic 01O0HO NRRj 4 alky arvy r rxy;v A. prestai- aly aryiw h Woryk artiL S0~ 1.moomxecehuideR X res sida C~t at Nay itfxrt aki V npxesenW CR yor N eposent O \(uGt ~s ad { reetaents alky% arys or am~1k; R Ft N SN 4
,
39 14,-- "Ral, R A. Mo. RSIt and,' K=o Rrpent alognNKR O~t OR/ NR~Ih Jkyt syi or carboxy; R represes H atyL aryl hetary aiyikv loOdt xnaoachd ligchrpide Y g aco ryly gopyrankod ygtuns~rstmi R~)~evrtsessK 'alky~IF" artmaryldkygS:zmo' aohad4 Ip es 1 aCi N Represents CRo e;N Z rer*eet S, C(R<Ne Na;n RK3resentr a &yvryir a& F "~ " "Ra R~ R R R aX 2x~ RN 40~~ R repent H aik ; k eteoa K 4dK ariy K~i menosaccessdeQi~ of goacchride gljafu vIy glvcopymawsguc'rvyt glnrnslor glucuranid IC rtepresna mtmy ee.ri ariloy.SI oschad ''igosacchaidergiycolianary glcpy na t iaonasy 4r iox ranidtgt Z.la sNts 0 S. CfIR4.b oxNRas :rd .Rx rset ra t vk, aryl o mualA OR R R SR' 41 wherindaepenentd foreachocramC' R s H hat ge t NL R 01 4 N t a y ; y rc d a y NR 42 aarpeny a ocon R is H. akyb agir1 haa~Crocys.yt heteary1 araimy;I -SOiJ~ H nosch de "N N Rs R, RR 43 vt4.riando adrntly fah eore RS iH W hakgar. NOtSN OR. INKg aiyi aryt:, eraktyt or cdxy; n Rt h11 a&yt ~a, tresy hetrctury21.ndkySOiH, annndui >"aadadegjndeny glycaymnsy gornskr gudoie AtA R 44 whtatindeui danysret ach~ ecomrignc Apresents Ans SKI Or & WO R seprsses H alkyl. aty awalkyi h ralka SOE a olioatphak lyefano tglcopnsd glueant.ns orndutyrnide; mn
R
5 r s esients F T NOSR OR aryi atdkyt ca R R .45 taeramnt i ~s 4'N o'~r St ~ I, rert~aoN t K (~N k Wf 3preaCR C r N; R R represent iJ atylwa. rylakyhateroaralkyo StHgmonoaccharides Ar rrssts a usdaryi or iaemryrin and
R
5 regr'le-etas. hakenga. NQ. SR OR NP 4 ityK at 1 salkyer caijc RlR 47 MUn idpne d nN eybod 16; amn a ,wu h fr p4a hs ~eri~ nddeieneuy Ihr eich bet nynmacR 0 m er \~N R i ' N .i~ nnwz~'~ ' 't' ~r~ xvti.X i'tVkt R As ' flK ~ 2X 2 ttt v wkLc& ~rgy r opom:1 alkyt Wit orwd vt SQ11 ~ dt KIT yonout ethylene, e' or'';t: ajn"w o ha When A{ i I)y m: D 1 1 i& it1 : 'k O. v R':. tR Wtt <arvl 1 1rt and OPt m1 @ ' R Ott a OCR U di n x. :iwte ci a oy . a oa d g a WE w a in t her embealmn totd ide manad i t g 4N'-ts hi. a .Cnr o Q l 5 2n 'Wndto ttttti Dell w D an M, mo M. 4 h; rt emod n h tath oincide cnta ting a -oll with atwting w"M conspoumn resttd by kna 52tfuat ddbnit whzer\t 'al' pn group; 0n11,i notegen rq a fther imnt w Nbt ntahdna edi with ac seuwdtg tptund represrtd by .inA. and x thitendantttions wher D is a phny group; S an tle ykgrt. otp; 'K" mr and t& 1 art 01 a fer embedeneVrtho umtods inda cta g a g 7ti\baet'at Cte2.pa'nxd rep fated by fendt" 52 an ' aCttndant ieatkio vwin AN 'la ite aiwanrtdh meI iaat3g a C4 ith af! aiz Oattn-u aangtsnast esented. atd C2 and the attendant dttons w A ethewwtyi K)edian phtv dag; RIad at Lid; audti$. E kh a ftuYr tmbodimen h m yho"s inlfdsCcontactng a eI witha ati dhuksmneisa p4i yinn2 ad Rq 3<art OH; and RI i, oa uner Antaditnnt tn tethods nad:e conmftEd a s w ant onWW" ecmapond reparesentd by {mda... 1 and tte ttti 3 adt c.tatns, -- w8 iw afhanyl; D) is awenin A; R st 1.4 are ED% O ad Q IaCzkCky In 'a ttther emlbaerrt; istnwthods neitde (onitting 'a coll wih as acianting etanpnd ;tprescteed by .. \.t3.na 52' and it .attendanM det.'dnsa wheen *ta AS is Merkxs; toI a phenyl am Alnd R 'are OH; andR M Ltayke Datbrhenra VigNW ana ar O<atd'z>is a caananftiia attnspwand ka$54se4e hy trmula 572 and* t 'tten.dlItdi~nwidas, wh.9a# theavlenc; D) is a.>.. phenyl.ingr n R4 ar'rOH t~aukdAisatSab.
Inafur&tr omcbodimm"t, h metNd icuecnntn el iha tiam oanpsund spreteisd by rma 52 and t attadnat dfnidns, wherin A3 is thsnyisln; D is a phnyl ring; 1. and "Are OW ad. b a 2hc thg roctnds inchade contacting a e i ana opomd reped by foporma -2 an theN attendat defntns, Wherin A-B is ethea ; D is a phenr T4 'ad l at Gd and R,? li(Cg; Jt, iS. a i)funr imbodnet the metod medd contaodng aee widh an andatm Iomoun ptyned n~by Rada 52 and thn andA m dKVK n wheoein AS R's eteyln;D is a, phnl(ngt6aidR H; an R s as a findwr (mbod(ment. ihe metocxis icd contataing a 0e0 wo an ciatng pod represtei.d1 by fortda2 an d St tend de ton hr A--h I. thenyln a ar OH: A is .. Qand R is Oie, snt r a CAI Wit vava 4 in compou n resntdisy formul 5.an th .edmdhnsns weui.-3i thnyinr; D a phenYt ing; R 4 is ar boy; and R i ( 1n a fourth enbadiment, t i itthis a naiing a clil nit an a copned :repremtzd by rninui52 and d ant Uitons whtswn A4 iT whopylno ) is N phsn'l rtgi aniA 4 at 1 (; and > is' easrtsQiA1 In a lurter smbodiment. the eneoduxs include ceuaetiu a e with anaiu ompoima represented bay foMYla $2 and the attsndant di~sniton, wherei A-T otheyee; isnpey aing R2 an it aQfl- and RI> and R';fj ~ ta -ogther form a annD as gn a eR d fan a furter emabodiment the m thodas: inicide eaaeling a ceii with anaciti comrpouand.r rpusnted~ by formala 52 and the attendant defiiitas, wherhm A-1 is ethnynesD s a hey ringR nd rehCs and R<s is 5MH. la S further~ t~mblahndCt, the miet(xx1 mdudS cotacting. a ct with sanacitn *:pund raereseted by formula 52 and the sttendat dstnitkons wherein A-H is Oeyee is a phanyl ding;1 3~ and 4 na OH; and R-f santyy i a fArtder emodimn mthds indadd oont adu a d1 wi an aaiivanag. compaand renresanktd by fnnula 52and h te nd. whervin AV arieyis; f) e a eyrlthenyi rivigand 1anagare K 4 OcKU In a fiwthrenb diriment the methds induide conmata a c2 with an actistin compound reprasated by f6rmmla 52 and t aL t tendat definira wheresa A-B atbenyicae D) ita phecnyl dn; and Ri2<and 14 ara COvi In a tirther arbodeneniN the IndAtd ndd\n a ith an aeitaiE podrers d by Armuka $2 and t attendant dftiosh ei.: A: B is. Dtnytene;iD is a phenyl ring; (R, and R" are CH; and ,iIS Oil I another imbimnt methods fighting a shtrin protemi Conprise wirg an attvatInga compnd of hi 542 54 circia ~ saepnenviffor <'c oXcUna) Qs Rx is H. or a, subadI~A te ' un Su ted anyvl afti armiky4, het emgelyl, e r, nggfirhetaoarv aorotcaty, sa a~ 1ndRara asubstuded or ansabtilued alky. aryt aralkyl~ herncyk t yk i helmary or hetertrokyl In a further cmbed meann he method :compris a om und of fna-a 54 and th' atendant dA~ddons sameinR a U In a ridbr emnboimneni.he mi atd comprse a compound ofikriwda $4 and the attcrenat efniiitrinen Thia 3rydroxyphenyt It a rthe eminP' ther metihods compaae.~ a opuda onlnaeh atendant definrian wherein Rz is mthtrA a frrdt'r embodiment, the metod ampde emound of femmia $4anth ettendan .dddn'.rnti H Uand k' ishdoyhni enattr . h~d.ne flmehoa opdae, k.compouind of forula $4 and the attemiant defitisons whereinU j:H Ral R is WhdoXYgpnetyt,~41 an IsaneiyL It anht embodyflyt mtat for ivatag asAda prtean comprse using an act tktat> icompad oftfanmaa 5: R~~ ~ ~ is1,n aa R 5 'I a unbtitaid okt amaeny, 5nr yy h -tycyt et y 'm hn rxuw ky'1 i ana tis 0, So ztNR in a nte"'tee a Uit *tilcstheenpnsa a arenop wrdlafTimidua 5 d the atendmt definition wheun R :n yt In a finisher msbodinen:is heshods compr-isa a comma of' fnndta 55 and the at endans dfinitons whereitx R im2 defrpey In a fatherr en diment the methods ccmpdasa a pnd of fmda 35 and te atndant definidncs. wheRen, a isethy sadttedant dfinitions whrein L is 0 In a fmahuer :nsbdimentthe methods comprisenvmaonmpond of fnnuth S$ and te atendaztledetions whermin R is aikynyl and Rs i 2tdihicomphengt ins a flather a hd eaLntthe ethos comppose a compound of famadia 55 andi the aitendant delnitions whereinkj Ri kynyt h is I2:,adlhtaoropheyl and R15is mnethyL hn a firther einodmet the asethods comnprise a amp undt ofarmanta $ anid the atendantA definition v. .ti R~ ~~-' 1Is aikyny a' is~ i*Adnhaphen4jP' n melthg1 andeis In anathsr rmodiment method~ s edvatng a aitt in pratin a mprise cabng an *acdvatiag comapound cAf fonimula S6& $ hn i:dependenyTrhy gtgurrence n . -a n tege un n a eduwsdvd n ~.far embo the flf ,6n fd natins hin R-,is 5dnhi1,hdoypey i a father amnbodt, the mthetda :i oapn n a 56 SOdik a tendaa r defin itioswhrina Ry ixxsN*. :gan diendant daitions whren i H I %iythrnbQdhusr2 ia i hmelds a a compund afaadf6it h QW wArTo ie I a AW mmoime the mthodn CnOpria a compmd aft6Mnaand Whe ndatnt defwidens whtaran i i v5 "4HeThkandhyd4'yphmyd1 i \ a ki1a ahthenebodiaxtt Kta *Pode Ytedse a OmKpun of iOxvn%(a 5S and tho bman at nine wheneti R~ isa yachbrn *edroxyphenyl 4 H, and R 1 i in a *3113Z$ emaMgif gh3A3 XfeutNas com a temun sfnua % nd It minda ateidns anheRn i RI K +iFO 121droxyphenyb 1 k H, R 1 iand n : actiataponaSd of foa's a9:
(R
SNa IT nr a subshokn ou ssudI alky &xvt aalkyk haeroCdV, R a subIto u d onisut'iat cdakyl aAtyi, a yt heieramyi, detarorxtI 4akyt eteraary4 or hebyankybv R-'A han o halk / a.h oelatr amnida, .kn m4o. v n yga i eidnirna oattner uaibstixnd s4 fig r staflkyt he Neyl s*eoq.d aky. rarvl.at nah idevskaaiegine ny is Odi5 Ardi.naoinnrs ~\ -a nm. is- anliateger fovn Cs 3ihv nis an') 0ntge Ren 5t inclusivet amd i an frinr frmc t inintb..ki .ar ndQ ouia5 a i la inhe stbadnwgth otds' compmis a conpound of fannum-a 517- ,d Ohe td deflitions wber&ii R is phnAy. i a :ihcert mdnr. im e nehodaeomprise a oar npod ofima. 5 and Ito atetrndait deftintiians wh4Obinds Fyi7 inea.hrthee dineit the irtad ra ct onpaund of taanl ind faa auenirarridkdinitions whe~trzrin iS \ Sa utiirdrento toet< the ninth vodtirse a cmund of .intenda 57 adnc attQ ant &finitins wai t :w Sa urtterubodslantNri t:w Zdsodic ampis comOiUnd OYNr $7 aShad attendaandaf minions wahreiua pis in a tAnermbetdcncanthe methods tomptitm a cratrpaand K4.nxnada 57 andit aihn diaa in'V'eme"' thodewtpile a coo apandofenawds $7andthre aucadat din~ns~mt I ispharnyl and Thi pytidin. $4 ia fixiner eil.he,.dunenkaa mehd cap sa-nm ompnd offmd adth ha fu hrtheormim ~ent th methods conUise~ a c oond of foa. 57 end the attendant dofindgeas wherein pR. yt e pyriin isvnna n ILa m iS. ,'ii ~ ~ ~ ~ i meh t - ~m In a harsher emboiment, the sethods comaprse a compounomd of imudax ana the~ atttna: defiitihn vherR is prrngi , Lpyrdine~ ILis 5,s as ta is i a ft the eto o4 R - uy\ -ej s attendsnt definitions wherein R. ph zenyt Reis pyridinae his S n is (} ns P .and o isa in oneter erdmbode methods for activadag a asrtarote n comapdiso king a R whreha epwiendy for cach occiiae R, R. antd Ra areRH hydnc. smina, cyvano.bt hdd ORY etht hertad Cwn Rire Sod ntwa subat itu . or ushg alky "arys 4dy eayy a~nd" I ertN 5
N
5 5 Sear'g ,Vi- 050, 6AlN*l~~%~C5~ 'h 'S .ypyoay~ suit mb odrenghmndtppxopad Lttendntdbitio5,nRsSo whCttisK' in a ftadwier modnerdt dedosose a mpud of irina.a5and the aiendantt defotiakt ra ' R '.a~ropheny' to a further mnhmdizmt th ha Thxp",dasampnd of tanda l and atd d dn hawe~iM RZii 4is tkSIopheni. boarhor oik tentnthda ntis a tompon of iumila19 a a. aliended~ deiioitiaoos rio R is H~ hIaafurthaer bonodimet daonhds comptisc a emiana i ofhxanda 38 andth anehn e~iiad r ei E ~i k Qc~~OOR lipc I L tn a I fdheambodihoicothe methos c mprise a c ood of nimad 58 sodih a mtdant dofif nsas where. I io S la enbad-imn t sneshode daimpdse a compound of'Sm Mmola ns taedine a no r emodhnent to methods compte a. compound of itMmhtIU 5 nd the In~ a ,-mh Wmoinndeehd copskema drmi58 and e ate da deIT ia ~ R Nt novieesi d k~is 4adUorocinnyi. kn a d rn h m m d Oemprise at COMpA.d *of onsa 5 and the attendant dcfantionahniio R i. isR i 4Rchlosphcnyk nd R 4 phengi LA 5' hthe' nmbodsxent the mnethoaprise a conmpoundf eondamit and thze da ldi aswiirein is H R is 4- oghnri. e is 4diod XOL an .ans Si a flather embodiment the mthids c pmrdse a comNpouTd of rmulia 5M and the attendant definitonnewheinie..is u R~ is sipenRz i44kremphenyti is il an ui isla H, l i.4 In a ttrlhar enboddoent the soet'da Comdse amnpoud of tbmrdsa 00 and te atendat detiniionn wharent i itH R> is 4 hIosphenyA, is~1 4-4blaropheny i Rd s H, is U, andt iS, S k- akr ocenient the mhads comprise a camipond of fomal $$ and the attendant diitka wh M: ei is 40 -cbiorophend is inopheayt. R i Ii & ~ t SO 5 nd Lo s NH, 7*5 4 ainrther anno ant t t cops a conae onnsn Sn te atndAtdfi i R Re Thj iS ittkittit4ompy R is 4ho Wlorophyi5 R to if Re is~tL ik tN~is $3 2N~t arid tg is 0< Zn asadrenibadiaab rthads for nhflsd4 .5 Siuin potee copdnSc ing 5 tivdrig comptnsd of Innula 9 N SNR heninrsu ind~ependentd fach cuas iiihydroxy imo Cyan. OAKld ORuthrdnandonae y he mnc 'vcalkvt hetroasryt, temandkyt i is H or' a subattuted us ah Ptad 9c -M cikyl.ayaak theartecy1 y iirst iant AtM X)IikS 1~ 4 niae 4 a subtie rusbau (ly st Akd eamj hemeydgiskyghclaczjari hetcraaad&igi Iyt al kyvk s mon&'- acehadd(e~ olgschri d ev-s glvfunnmosy gli~yrapymnsyt 41entonSW4 OXgiuode Lis 0 N~,or S; and a is steiateger hum (} to 4 inchsid~e a ftft><r tak nbodieti the meIbeds co,00 a compound of fbnula 59: and dte attendkant ddintiefwhmi R; I meth' ,"a.z r-s lnbOient e mothndxa OMPAne anmpound. o+ forntia 5. -aid te attendant intiots wdeai a is to a Tihr ohiment aatdd cnmupise a compound of £nda 59 ad to aedat delh tions whomin R is3ffaphsny <a a fardher hmodsriat, he method amp5U4 a c.O125m dfliotormida $9ad the atedant detn'as Nwomine is K an a ht tab lme~n. t te thods wonme a ooutond oif fonnla $9 and the andand anr a tins% were a 4 h p hi a fhrther Anhed method camproe a enmpound of lamtur 59 and the attendant definitions wheseta Kis Oviv adai nz 'roer hnibeenrtae r Ihds eConpdse a :cA~jOmpmd or ai 59 sad the attehdn deiinidnsnaanKs R :methyv i and Rs V hifa tttherem hde the methods comprise a compound of fkia 59 and the adentia Aetona:Uvau a ithyi n antagnenoheg teendant defain wherein H>a nithyl n is *ttiR naarpheafi. nd R 5 s H 'nf rhemodimentte methods cmrise a compound of o 5 nd die atendant definitions wherein K is viiht n is RI K 1 isarophoryt Rs isa iand R 5 a 4 chlotaphernit in antier embodiraetmethods kir activatny a sirtain protein comprise assig~ an ACantIng ccaoprm offtonada 6Th R LI wh'exe independentlyer each e K i. d Rie: Uor a substinuted or uas tituted aity aryt, axmiky~hetermcyclyt or:c ba eroessdcvTkN and 14 ad VL . ylak terar K orna S handU iNu, 'and or in . fadher snoinnent, thmnavmbds comprise a cryrmpatwd of f~raada 60i and the attendanit douvideaos wherein1 K i3methoxypeyi in a other embeodeon nt. the mieftode omprisea cnmpocnd of farnndn 60f and the in a farther embdr+"ent hem ehdcma a ax. n fnasa6 m i at'u Tdadennions wheareiWn1o NH. 75 a er iebdnot.t motand com'is 'a co pould oind atemmn dnfinios Wherentla is a atdnt donrilat us wh eroein R>' i -"mehoxypheyl and14 iseut h ty hebodneih, w d m ofa L& ,-LU'tA 0 a tIs -I)Wn f.- NI~ 5,6, 1 agndanjt detinioiis whereain R ih >reihexvrhiny RA is A4fbinhnyA an.d ~isaNK ia fardir eomr nrl :thNd hwids cop$oacn 1om of inmaa4 and thez isl 0 in. another ehdtnen tthedd$er acc#&t og a airtda potceevpie usingan a'ztating0 cn4 of .frnadei 61: x J. Ori R is R' hvdroxyawain, ano, ha~dmxO e b .er. aiid ketrone mrrb'o Ah: it~in er 'S ~t\Su ittd or en~subsudeIdmk.yl a v:. iii ahsx 1ertoealit hetemn oyalyhdki ovo'ry or hImaky B. i H or asuan oe at anthe aktj avVy Tharyl heterocy'dyt 'ctmeylAlkyv 1 hetemoary, or hetemaratkylz Ramz aityl. SO ~I., N nanChridg oiigsaenharidc Vesgly Z:OfuacyL giwo vraoo' "yi xo~y. gltondgr!ernd an am Iare 0. NRh or S and an mtieer frxms d 4inhn hra futher ermbodetnent the miethoda eoropise a or npound of rinna td and the attendant df1inmms hr" R smh In a faitd ermbodimntad. the mihods coaprise a compnd of f 4na 6iand ie arindant dtfintons wherenra T jfl a trthewr emabodhment the mnethodearrie a. cantad of formnda61and We matter dant definlinsn wherein R ~sA54ideU dh4exyph In Manr abAdimentk molthadsa pra compound of om and the altendmt danition s whormin 1 is S, fa tdher emodimca the methods aonren compound 6t 6f f aid eth attenanst defminons whernin L is Nd In a idr he entaal te methods compise a cimnunid of finda 61 anid the attendant defiitmos Wterein R i methyl a Ais I ta nte ejnbigdient the adoaprst a tmnspound of formuda 61 and the attea.d.d definitions herein i aethyt a is 1,and Ra i 1 4r-imethonypnheng in rariher emabodimcnrthe mthod compde a compound at omita 61 and the Iniaf th ebdndaathedti'"aiC cci oe a caiipound of oted 6ad the atendant de~rdtions wherein R nae~ is unhy n 1 4 ~ itame:oyphenvt is S oe 662: ahi nt miar eths n V itdide tis;a eerne t ramiwok kasecuti y dr( o1nonia o. gl <rd Land Irt Q NO, or S; and n is an in teer xro to 3 1nu*iusi ia Ama a ft mbodAn h, m ethod co se a rsod f fbnorda 2 and ha attendant dannit'Ywere~in a lrthear emlbodimenth, tl metSods comprios a compound of foua diend the a aheonbdhstt dotiiin looa~ ie mto acs mph smondo amddan h a~maru 444m lk, i.' u'l - , hm'es.'\t ttendant deftons whrttia Rv f hi a other nhOdAv Ae dIlthodt comrpise a como affomnukasnd e 0 d04IO( defnilns Whersi Thi S In e; elbwdimnet, the nieds ea opin a cttpound f 6nma dn the athtsdart dciinidons whereno is 0. n fureur em'bodomen tUhe tohod; mpris a SO compoua of ofa 62 iad the eas defWnitions iber in L is O, i a finther mhedimnt. the metlho rpise 'apo ualffkoia l62 sd the aStndarn deA n ins whnein TT ~i 0 i in a farme.eehodlnen thrfhd sane copsond foranc'' 62 an the aindarH daibonEe Rn iR Es s and R isp ph In a irther enbdiment the iethods comprise a eQepound of fornniA t05 attndara definitions whein Ra ft H is~ a rophenvl and R'.edI hi a Anthei ambodtimemi the eThod 46 omp\q4 s40a temoun of tf~oL4.ad dian 50s44 Stten~dkit definona Ihi H4 R P uperianthny' RV isa H C an R A '. 'a . faterabuaEn1t taxi IoOmphae a aitpoind of frida~ 62 ist the.4 attendosnta ttion lwrari 1 Ri Had pe ns'uoropheyv 0 Ra k-yi.0s H' adi S 0 i a tur'ther embtodinet thde atheda comipdse a csapoond ofntnal 62 d die attdcnt datinioitnawherein R ~a tH 1 is pedluorophenyt R " it Hs~ Ra s1 Mis 0 and 1 salO in a furthr Aiteant, h methads compisa a compound of £omrda 62 anod ue US vt rdut i , periakorophenylR in 31, H i O i 1 In aI Uamensnen bils fCr nsank i pwtdn c rmps g ab n ro IM U x rrtap" O daW ton4A anwoas*1 0 oAanace'ai rroyino i4 DOWra Omwor a 0 n>aii d s or r 6 idal. at, arlkl.heorcy 1Marcvv afv W o corto a ijs anhoxyisoranatirasttu te r unsbLued alky vLarly rarvoinhtm iy heleeydyaskyhbeeroary, orherteraardkyi; Reis -aikytS~yLOrononacaarie oligosoccharidNgiyaotrsaosylK glyeupnmos gucaronosyi or acumrnide: LeVTh ~ ana Ware .NR& or S; anid cc aind ri arcdn gers ni'am I)o inclde in a fadheor aobodhnche a nnte ma ca panid fannura 63 anid the. altendantefino whettin a n i Inn thehr hmodimeA, the mthaiacd rma co ieniund of fomnadnd>rc the attenidant definidons whercine e cyn i a Lo tL&r :embtdettOi thV methdSCK isagde a compound af-N foml 63 nd. h aundatdtimairons whertan .kt hyS hi a iwther etnixiKnen the aides (ongrsse a comn)d~ of AiruL6arid the atsendmnt defnions wheniu n : is O sa In a 6iha asnhedimenth i th apn s d of fornkad 63 and the attend a dbt:hiain5 wherem t iS O In a nhe mmbodiment the6 methds comptisa om t pomad offrmula 63andku ~~atdndt distitons ~ whsnis Le an0. s y InA farther ambodimathe mewwthodts omprisi a mp d fonma.a 63 ald the zakk-datw deawton ereia n is O i" ean anwlety ~~~~~~"i and4It cC~ A. Ia fArlmo WWWS\O V ..- ~ s)4 1 A An fitheo bd1ant hm 0 m pi aM ope ot fornaa 53 and the anetdano defitn ian i is 0 R ina R is TtyO anda isU0 i a0fm4he 01mbodima021th methods~' Zcampd~fSe a mond of ama and thea attoaa doa toics Ih '030 n its lb UScy0u110 lb11 thyt 01 0gad 8511X1$ .41 14tli~ fh(3mboeetabe et ahods '4ompe "080a oonnda of .Wrmua 63 and the mtandont de ona'horakna ia is It is ano. R, is mis 0 m is Oo and ti e e a fud aunmbodmend. \method0 0ot5pr0 a uompound offomu 6 5ni attkadant cllitioneinais isdwsry.enns 0Ki4 enl as AItI S 4 a s 0 ad iL M O. uuanotheir adimnrot, mnd It t a.s a anas prntahn oaprsus ag atn acivtng comrupatmd of 6 fmada 64. 64 whetasu 4 indespendend~y for eiachocanc R andk are Ihydrxyg aino~eysana hide~ OR ether. eatexgemi~do. kenne caraxylicydditte or a substituted a tnsbsitnAed akyt SKaalkyl hWterocvyft heteerlydkyt hetQrSYrd or he wralkyt and RA ate Ur a a batnd or em ubstitedalkiyt startel.> hertiocv ls1 hetaer vlwk thteroany, er heylroaralkylt acynvrpyisy ghiouronosa4 r ghiuroide; LLl and L N a, C r n i an inelgfIom 0 to 6 htsi64ve; and o is an tnteger iom 0 to S inchsive. in a farther armodimmt Uvs methods comprise a comipound of fetmala 64 and the a tenantd einitions wheresn e S& In a father enbodimeZ the methods comps a compound of formia 64 andhe attendantidfiions whereiaR is Ci and mis hn a ftaenr emb.dinenttheleeods comprie a compound ofonula 64 and the attedant dintiona wherein R s #bsehy4phenyT. iha t Arthsen~ir Q ucCnmt. the ntahods comprise a compound offmada t and the attenndaardefin ins wherein U is in a futha ten inna the methods caropn a compnsad of famraa64 and the> atteadan t defmdons wherein64 "md in a frher rrodimentihe methods co64 ",d d the) at mdefentins wherein & is>2b4 a auehcr embanfune themethonsempea omop n . a odla 64 wdi '. atteant debatwos whement~ Lis Ni4. 'in a further rinbodimetnt; e thodx comrpalsea camopond oif fnnelsarad the is . Ilk W1 ' "R~ 44 La a farthr embouelxt temtdcmps a ompoo <d of fa hUi 64 mnd the waendats iniio yhex n is 4t RA is enemywt is . and is 3l. la a .fiathar embodieant the mnethods campdrse a eonmpoundi of Amedand ad4 the tn da!Adiinon whr. NQ is msethy! m in CFm 1; and P is 4T in asinther embodiment.he nethods compuse a cmnpond of trmuia 64 and te attendant deshfitiocns wherein nl it s metiwy R2 is Ct, imis A; it is 4-mhyphnyl; sad Ljis S fig finter cmhodimnat he mthod tvemp'ose'" a compud of foml 6s4 and the attendant defnitionswherein a. is <K.Ris methyl Ra is CP 5 .min is:i R 5 isa4-oethyipheny.; is S, and ia U., in a fthiher Hmbodinit the mehods cmpnse acompound of famad 64 ad the tendant daatitonvn~ herein a a 0 is meAhg P' a 1 R m is ;a is 4.methyUlghany It a fudrher eintedinient hemethods. compie a conpound of formua 64 an thim attendan detfitdons wherein n is Itif methyt. > O'im is R.ii h h {aiS i s 0 34 isNit 55naV : it another emiboimeant~ methods tr sotivsaing a stiin protein compaisesnsg an eriatis g pond ofana d5 nherein independeniy for each cmntrence' R mt a w bywxy annoeno halide.oR, ether, err'staidktone carboxylik ani nr o o r d w nri to unsubs d 1, araikyi.$te ofayt, aeteracydyalk seterary'i or 3etermaralkyh R anid I< are or a st&stituted or tnsubstitned aikvi.aryi amaikyt. eterocydt heteroeydyihiyl. hesemaryt ortr arskyt o s 1tgis alkyvhO 4 i0B4 naccaidag o tosc4hadde glyoofa:anoy TyCOpymnlOVt aiytgcnenasyV.i at him.nd an Sadeare. O4Ra. orn Ia Attherembodiment ntxeod coinprise a ropound f fhnwx65 and Ie attennt deenhitens wherein R is cyan i a fturthter mbodtwatn the iindtods camipise a cotmpoand ofomdat 65 and the s:tendan deilntiana whean.ILR is NW. na e imbnn6n5 and the a afauer mboingnt th meYeds asmpse a com pound of ftmada 6$ sad the eatn dsi ons heaisi iL vs 34ydr'inttyphtAn. hafu 0herebodasa the Maee4deunmae a apotnd of .mida 65 ale itttndant deftions whe4di is D Iia qhutor vmbodapet Jthe iethodacrngdsaa cmpd at ionils 65 and the tdoda ddtas asyn a ~is toNIL. orW diendanadaniddnsavae~l tNe jfl a thanijp emboime the tisthode can)p$ s a ompound of fornda 65 sad the atenan definitions iten j i iyana and It mdRis .atgher embodime~nt'ea miethoda course a-compxad :Jf fomia (:shad the artst dCeishenS whrniti vyananI sa Nit and 5&is41>rmnphenji. hi a ther ambodimn. de manhedsomaisea comeound$ offimulao Wand the attendant de m shainRin isINit AR b p a S I a farhembtdanait h ntfhds somgdSCa campOUnd Ffom a *35 and the ateendent dzeiins wbercis sayano IsNkHaf Ri4dnoophenyid 1 is hdr.y 4-metthoxyp~henyL and! 4 s d. hi a iafner einoditali the ins hagaprisn a at around of fanmadS6 and the attedant definitions henean .R is no. d i NMI% 1 is 4lwomopheni. PL isa3wdsyda 4~metgha ywanLgdis K an~d L is NRa sa.
lnatier elbdUeilidd , ctvti idia preidin cmigsuisa adhtiAung oopomud of foimea No w whereinirdapendentNy &r aachk peee R. id a suwobada or ursubsrtuted a %y yladkylt aaxydy heeroaytyakyL.htroaryL orhtmriy R is hydroxyanino cyano, haidex OK. ether, ester, anmdoe ktones aadboxyica inaor a ubitutedd aryi.ar yl hetecydyl taralr haty eratlk Ren alyl, Sa mn n Add lgomaehadde, lywfmanosyl, dycpyrnog ghiumngior ghuonide i jNh and Ia ara 0QNR; org and n is as inger fukt 5 icludi I h SanK 4w naThods comprise aompousd at krmntdo andie Oiatndant denni hius wher3in (CO)G in a turthzr ambadinent. theadhd op a copudofe: s 6 n h attendant defidrns werisrL' ts NRt in a :5xther ambcdinzenh methon conna a ompond of inoata on6 and tba atfendani defnrin~s whernin La is S. n a nrier aaodnanatta mtha sh campdnrie a ca pound Kof foranla 66d and ix aztnat di nideons wherein gg is >UN inO D1, n cm denn i;lr tos wh w ft- tfum e boyr! old R is WQDCH, ina rther eOim e hd n a onpntwn at d ruia to nd thi t d ad fitul WharAt Ra Q r4 M h he i N C o)'N dL, a ima~ emomet th ehd mm a copondofnoda tnd the daft dit~lietOs wheem R i tkdiN tlphen R W iCO,)Cs & N a L NR s tafan ernd andned _udetp apen ; annu 6 1 and >J. d N S. Yr for it a pd ' p a na ad the whar aa . .R.n js Th flcad m adv1aa n tR P C a}XJI N n\ N'4, $. andN wN wt, naUe iv wHtda and to audi ttitte a orian ebidai~ aa dti h a lkiraraupnflt~t t tmoyd a he vamg naande 4 A her .. A oan aRis akyvg, g! mot#osa'hadde algscad eomns p ud aure aos or I and n is an imegr from 0 to 4iniive ia a further embodim~.~en iaethod comprise fmpou nd aOmtai and t Aitandant d t midtai'Whini 0n tn a fArtr admduer tiamatfnods ecmprise a omp sod of ibrrahJ d7 and the attendant nnsi hreis 24ttahytirnyhkv y4 a fusrthar embohdimnnt ta methodss zwco mis .c mponnd :aftnmvIl 67 and the ]I anbdm athem e a comp talsO 5. onrpo unpd of fbntia 67 and Ai atndant deAtions whain ns h A furt.r abtodanen the eheaComhpd1s a comtnd offroamad dw tme attad~at dotnitions vwhtn is c NRb In a ftiberebodnwat the methods coflpdse aenmp~ound offetihote4 and the iva L futer' Anane tumta Comuse ia compo"-Undcf fnuaw M a,~ tHCgm Adsc0N0 miQn is S In xfrteramodimentt tohe~ .... niehos cmpis 4]iennwu of rnna 67 anddh aet def iiion wheran d Rs0 is 24ewahydatfranhnetVhnd }s i Ci3C R, is ind 4 T no a ar embodimenttmethods o onadg a 'n po m usn aNn H nmpun fr s.. f R 4 RhRkiP indpned for ilch miourndidb R~m RAY ad toore toydcywandacaahieOs te sn amiky I~~~ ~ ~ al toaeA oom S) Itndrbr~ J'dar et "n ubst Roed 3rdastne ainay aiy R i m alie r~.nnuas ci Jimno g(y)on tnos 5 gopn gtarxk i w o tronain orrneund afide 68 cud darr v u is 1N or sadi d znsubtinnd alky. arykd aralkyL hetrcciyg hetrovgelv amy hot Naryt or hete edXmyl ni ditgeom I O-R, M AS I, m A a ineer fito 0 to 3inciosiver O s anxitegrerfron.iCto 4 inciesivo;so nndmntth d cmprise ompound of fsmoda de and te attendant tdetions wherin n is CL In. a fthet5rembodent~ rhe methods ompi a rcmon offeim~a ' 6mid the atendant dftimons whoeei mo ts I in a tfhfr kmboimet. th metods ctrmpdnse a om poundvof farnula 6dtand rho atendant idnidono 'whercia i is CL 'In a ktlr embodimvQxtk eth. thods i :ke a cm ofat fonmfal 68 and the atktndat deftitions whereim ois in a fnrther einbhdim~mt the metiodk cops cmon offoriiaN 5 Jnd the attendants efirdtions whe eia 1, is C21 In a fiarthier ansbedimantte methods a compamnd of foIunda 68 and tE attndnt defiitions wheran igi Es a (inthar anbdimentha meth amck aapu a compound ofrtdam and to MUn deainition twtin i 0a1H or i Aratr enybodmaki dhy mamtods contpose mpndffnna68ade atterndbt hniti.ona nnyin im : ad in s! In a tnther madtnt h tosicom s& copound off(onuts $8 and tEa Adneat defiuitlonsaereto is 0 IiMs It is 3 In fa thnt bedsmeinant te methosCamuprisc a coampPO06. f1 indaged the attendant definitioa M whrch n is it rmi en is a1 sC a further A~admentehe mtode conieriso a compound offormuh 8 and lba a'ndant. defHins wherein a s 0" un ii Lo 1 ia ir.and hn afurther ens odimmet the cethad aoimpise a camp od td E oda 68 tad the atnent defntin whermin nisP O"a ikois i 1 is At p3 land mid' aret aTh'e kmbodinetmaehods or act inasimrs protein compose using ao at~ivatirng coampound ifdnnda 69; 69,' CP Q 69 whawein, indepenskdy tkw each entrance and En a MyobR&d ordRk ox ai tivny mc i! Nhttr n0 41a4 4 .O a ner abbe gods caps edan b-., in ao o f Mu' 69 and W, in a4 Lotb n dn a a tic 4s henpriee old . t in2iothy ! Q; w hrtba 'Irxho d p a 2,pon 01 kanwb t ia .'othr mbodint~o the :nethods Compris ctspownd lof nada 69$ oadth a.tonowo +~i m wl fin i, 2 P. is reh or t bhty ITi R2, i nthtlyl Or tAuvy Be L i 0S In a .nu hert smotoo tatnz Vnodst mpnis. op frna 9ad a dis 0. an ortoanhO} tineunothoeorat inadaapo i oj'a uue whcrctxtindepatOlwZy f or ash onrrtdtng aIdan ke~okme canyuc'" dtrc.o sbs tkIPated or onsabtstud aflkykr. arymrTkyi. veterac c hterooydIy..akyb hetraryvt ox eaasy \o aI~ uflated' or flnsubNiN a dklayayadg eme atemeaolyhokA 4 hartdk.y4,ohcheoecycrayky
P.
5 is aWJ.4CX:W oosacvhatide, oligosaorhddetydernd syl gly.optn. od i-n: 50n.sy or S odn a) is~ 51i0es 0 (U t4 ttinetava attentdSat i;eP:niens w heeit nis 1 fuisAr~eoembdimente tnhaOP0 intods campse a compound of oramian and th atendamt dafinions wherdli 5 i nmahv in a fiaudr mbodimetima mhod p a cound £ana?0 and the a t a ondani wIat R i NmpO)OC70caw the I a forte; enioduarN idte mefthde empt3 rmitd .Inm-ntua 70 and i a Ada tlnte a4 awerin R is C(O)OKu nfth~r mbodins the mnthOda compile a compou aMWtrndn 70 and thm Wn a SOnton mbodhne to ueinods amphyuo a ccugcund tgfftmna ad th attandant &&Atidefn WeiYn RN is C(O)Oivt :a ertbodent, the methods cmps a tmapoud of f hmm 7 and the attendant definitions wherceN is S.teh in aifltherembhodimnen, time cotmp's a ooeund ofiomua 70 a the hl a rtinitiona herein R LI anfurer embhodmante rmadod compdse a c aopound ofetmula 7 and the iedanit d ildns whiurl ts I(S ) n afuthe embhadinment the methods compene a mpound of faRada 70 and the attendant defantiosna wheretainsNI ad2 nt Inafre tmbdinet the niethdt compos a tempound rf fosmida70 sand the attendant dshnitions wheein a is Iis nehtsr >i (}~t h a inithez embodinment the methods cadea compound ot famada 70 an the attenaa definitions wherein a is IS. st'R (f(i5 i.R sCt~ It f trther embSitset. the methods camptisa a cor ound &ft faiudW20 andi he attendant dinidiens whereinan is IRP is medhy0. K is O(O)OCHg.R sCfth and Rti i Innt fate.mv'th etoscmrs opun ffrat0add ettmt tdJadtiam wheein a sP R is aeth;A. R C(0)C s Cs(C4)OO R in a tuher embodtiment~ the methodr. compsise a ompo~md offomunk 70 and the attendian: definitions wherein n is P.R is me{Mhy Th is C(Q)OCftI ( 2 is CA)C m 14i C(OGtE RAt is C(K)OCit. and R is mty W fheemehod o e a compN of foria 70 and the am di~thon swherein I . R i ys to is C()OCmo RO is a az funhe embodimnen, the methods compnse a compound of femmk 70 and the C()0C11 R4 is C(O))OCR.
1 is it methyi. is ani4y and R? is 1(0)9%. in a rather aebiiment, the metod comprise a comud of formulah 70 and tia ieedan defnitions whein n is R1, is c yl j is ()0CA n ;s C(0Y0C7i, Ry is C(0)0C> ix4 is C)bCHt 1 m is etht a Ct*0('A and L is S. in a turther embdimer, the methodl comprse a compound of fn 70 n atte a detaitions wherein a is l. R is mthyZW R la Q010 ',I ~a C(0)OCH't R a is CQ)CA i i C( J)OCH 1x mety is mehy RK ix .(O}C L~ ts Ii, andI ii is ad. atainewhui emod torai 7 e d aye wherng ipndedently fuba auca Qa!10ae hydmmy anino eaaule isnse d one abo acid, an xy, a substdated sylsimkyOx hee \cdt aetnv y yctalkyJ heteriv ayer h$tetuadk 4 is F or a s baiuted or udnsutbaed alky, < anky htr y glycpy r Anosyd cgiutnosn r gluIcad t"hn Mndant d t e s h; :ufbhr embanimetn hannods cocMst ropond of nwuta 71 he! Q Weidvnn 14h,2 muwi-' r nrn' atW I K slvAant defined wh is nahyL in a hnfwow, exmbhd iment amhod co m e a cOMp iu 01 A nd tt onnda ? Id te atMda dftnOns whe:in k I{O4OC11 i a Ottw aimbodimengthe methads ecmans a .c4mpound of foama 71 snd the as{ Sx(atlefonbla inikxp (Q lCI - lC tu er xmeenn Pt AhtdA. aoxise a c n 0Ad tV SOt aMa 7 1 ad the auenant & idenuon wberei~n 'a s mis h In ethtzebriia f th etos comapuse a utpound tsi malta 71 and the ttteodsan daion whse en JR isx C'b (CH in a faueb etnimnyet e I~ meaos comprse a entepanadt Lffenta71 au the attandant dttions wherein k> is S In a Turtheet tdinent the mrethda enomp 'at a ompound nfaientna. .n aniTe alte.tna: definitions whearen La V 8 ly ir "> 'aav ntoCnl 9 p-ound oxffbonn~h 71, and lbce doe e d thbehds'- cmpnse a cmpoundfimaa il ndske ateudant definjions wherci IAisS Int Rheniwea odmbedhn the methods comTprse a compound ofninua 71 and Ch nttendmt.deunidenswheoianien d Kisnnetihyh in a another emaodinerthe methods pise a sompouand' of fmuda 71 and the atmeniant de itions e Ioin i nithyi and P is Q(O)OC h an a their eb~odmenthe methods ueomprisea compound of tornda 7 and the attendant definitions wherein n i R is Aetyl,& C) t a P is C(O)CHo In a fiherenthodimentl the methods compise a cnod of tonain ? and the ttedant definitions wherein is is C ) 6 i i (0)0I2k andR in a farthorenedimnt the methods conmpriea om d of femmei 7o1. and th attendant definitions whereinna iR is 1, mi ps nsethR( C isi(0),Ck 1 s a b miethyl, andmidis ie1t In a father embodiRentthemethods compise a comnd" f7 edA attendant deiniiensawerin a is 1.ftis msethyi hs C(:COCn Ra is Q(QQ00. Rhiis methyk Ra is methy and R
(
s is CyiC , Inafurher mbodiment, the methods comiprise a comtonpriad of formlwi 7 and the attendant defidionsxiherein n ist PR'i methytile ei C(Q)OCW. Ri is O()OC~hefel a ais niaethyl Pais CditCCibh andi L as In.a fnuther eandidnat the methods compass' acopounad of Iosuda 71 and dhe attusn~ t deaidens wherein a R1 is e methyli 1 i RdC(O)CW~. his C()Oi h is ameth is methyRis C C( 1 H t and Wis S ; in a uthler ndmnen t t metods comapsses. compound domunnda 7l nd the attendant defnntions whereinni s 1, Ris methyl R is CiC))Odlile is C(O)OCi:L Ph is iethyt 1(4is medyl Rs is (C~Cfl4% V isA andit is& in a thther embodient, the methods comprise a compound of'forinala71 and thus attendant defidns wheren n is( iis meethylk~ is C(O)Ct 1 is C(OtIS K~Iis mnetui 1(4 s mandr Ra is CiC(s)L is in anid in i In aki fthr en.hodimtnie te mehods %xrpde:a copo nl1 and the Attenat definions where . is , is d 1is CtQOCiA $s C{}OCua Ri is mei Rthy is meehgd R a is g(Cih) .
1 s Sai Sr~.5 end is S in anothaembdintmothods fo activetaR. a sittingta oprije s en eating enmopnndof formaa'72: N N w' R 72 whea rein nesendeavyr carh far R nod R! are ydoyy. onng yasn halsdeOq ehretgm kae Qabrxyfm aid rnnrenwhbaited 6'n abstnded ativi t.staUxthet~o~eneyl, .hctcrmey~ellky htucadiu hteotentalkby P, arsy mne e-n t aik ytheresten amido ketont, a.th to re acida a eubsdt~ais or onashtitoted zkyl, ary&k atndlhkyitcycly Sand toone A NO vRwyorg is an rf 4 onclive; nd in at ther emJb -- a,,,mtnt tbe nx:maa~s compie ax -umpvund d rma a d thet i as n:1hr enirdetr ante athad gcamp;i at aoiIn ornryc&n1 h a dan dinteaa Wherei. n C fi ThaFahs thdimnth oh~entraea&onpw fitoi 2 n h Ia a dermb m hops a72 nd the attednt denitins where~kis 0.. hI a thte maimnta Inmecthoaissas a ngun of feuddn the attenmm~t dfintonn vherein 1 is cyano In a father embdnn t elh e imsode amprise a u fbrfna 72 and dbh 4tandant defiitonsywhtwhintgisS*~ I a further mbodimnaihamthod co mprse a c of faula 72 and the atda defindns wherein Tess & i :nhaS the XtbedII1mthe mehodIS copis eaoun 1rfmlIS2 and the atNSd ant deinitis whesein a is and RN inCQm a Anher e d h hodast compse' a enj 1 aund of OmOa 72 and the aitectdant d<enn iensavhermin a is is st ina ini s yn In a tnher ani>dinaem then ehds comprha. sampaand at' fanh? n h attendan defnidins whexmin t is no i K ci 0, is S is yi hI a father enoieth methods couprisas nr o nd ot' fona 72 an~d th attendant ddfinitions hereinn ci'gi n Ce i iaJ, i } ynoZi an ga Inanother enbodinkan methods for kedv ting a siradn protein rornprise gr not'i5ung compound of ih& nnla 7: whmi inpeagr y.fo,.. ocirnrene R andi1,atehdx andnes eyno halide O1.eherstesradketne. saXyhel i asiro. or a :tsuxdit or unadsted st arni, araikykheterocyciyL heoterocydyakvky heteriaryki or heteoamaikyt; Ris alkySt i tunsehdd f2.c .iegycfrnsi g4yeapyanosy. ghteronnsyt orhand; n i iee ne to~ 4 incasiand v Is an int aitam o t . inalsivQ l a ftbhrlta Axoc a ith -,odw e omipuasvud f frmada 7 andh attendanidtanwhein s Ia 2 a afinhe emednen th mdad cmprs-a Co=mand ofim 'a73 and Mh attendt diin wr R ii Ci orudilTaismethgl Ta fuh thods Cmpus a cwponr (ufid finnuhk 73 and ltt attenmda inidweenmi In a Athmetr mo th d compxie a m n of femmianand:: d d)in he r n inR 1 I p RanysF In a fAth n todoa w th ea n odal 0 cam s a cmpaumd of =Wra 3 aud thO 4tonda d fvndens s erein ai2andis Cl r tfhommnet U a rthexr e~anbdimeiantrhmeods comprse a 4 co:mpamd of :mada dth atrendan defiition wh un n is iCotd*1, 2 dbF an m pi ml In frrther emoduatnybe mertods comprise a~ oipound of thrmtd7awlanth attndant defiains wheren n ita R 44 Ia r tciloroetbyl m is 2 anak~ s pheon hefuh. eboimnth meheA co&m pd cmpun of ihmd 0 audi I the attdant dotnn inaswtorein ua is mra fthebor onmboditment. bha Amethods c'' - a compund of tammda 73 and the attendanmt dinnions wtarcIn. is 19 ine funar mbudnet~tenatoampd a nomoun of toranlan n h aateda t definitions whorein Riis 4~nrthylphanyi. LU 0. furtae' enx)diet n mhds comptie a comrponnd of ftarnula 73 and the attendant definiiions wnrot a is n d a iax ii Aoiart ibidimnthe eta hods conxpjsha comipLuntd ofa foulna 73 and the ailnnant defnitken. hereno i K :s an m ba.>. tr~ embodmuent the etod comp'f aseA5 a compu oUTtf EOn1ada 73 and tha altomdant danninon wvhamis i R is 19 t a sA nd is 4meatbytAxngl R A R in hd Wf 4' R~Mev isV~ SA t-SCI, rhtwovemok NR ivAJl e adutdatene ntias hdi~: Oat halr.uexn het a ny It h ra cc esii 1aI:wra vikd l -Cr. r.M~\ ~ 4~ .~Za ~ ~ 4'4 ~$kXN~Nt 4 N4 {~tr ~ 7 w{4 a~~'a a In a ym 104Mi e het rocyc pyt, h mydyay he0ar0ary r be r glym yumosyt gx tt@oos itr~ gicu7 d inatuhY aco.u 4thn< etkcds pc3 a c(non fcrO74amdtn Ic nerthc t 4 -'n iht a e ~ c%~. radscngn t. si un 74ad 4i ht ttrttc tI~tt tbos Ip'~ d ~ nmpdtnc a oatVtundi of da n4 he acdac~< datdor Wdu8 ~ In def n ausm l m it in sf Own nO In ui nn i c CrCH R sad ftny~'4~c dan' " ddoende.A\:R MdMCh (CR fe t *~f~h)t41 lnenrs WiAn 4, tbc 0-I Is ~ i k Qy(0QH' aQ in t1md ' and attda3ta~ wans 'varow i n R M . to5 a W~kay amtodianan To mAh(Ps compry a acm~pnd of' itnsAw 7- and h *, 10'N us w~yy m V o Ia furtha smbndinsst.the tnethiods compris 5 Camfpoun1d of formula 74 aflthn S is 1R, itA tois alkyiys einzisan in a irther')a amdiment is iethods sompnse a compcsund of fbamahia4 and the ashdni d fanitiens whoein U is HCH i, Rin I, is SilkynyQtw. lb is: OS a4d R is C(O)QEl I a suer eMbodimenihs methods om a5 compond afUtdC 74 and the attendandeznians wheeiKR t's C. CH 3&VRA 1 -A is ' 4Saiygieem OH, R is C(O)O&tand I in a Antherembodiment the onisdaise a corapound ofotbmia74 and tie attendant d.finitions wherxehnR is CHaCHMHH n is R.5 s I. 5 islyyln i >'i tis C(Q)Olt o is 1 * and R is q WI. Ts aftIrther embod tm ia the mthos. eomprse a oorpond of m adneia 74 an hne attdantdeuntie whedi Ro isnb bD is, 1 i Rlkn,,n - L R,, i attendant def 00:4ns whomin is &CHOH is WR RCis is alagynyir n is tRAs OR R4 is C(0)Mi. 1 his O is and s. in ttfrther ebdmnheeth odS's comprise a 5 amponed*'M~N ffmis 74 an h atndavautde flone wrheinit R d*C H4 2 OHi an I R5' &ngi >iknyl m n i h erta tim reni, de methods otnpise compound of fbannla 74 and the Of ( a is U Us is C p is b8 0, k e y CiHK RisC(O)Oii o is LIK is OHt p a Ciis NH lI' hO and I' 0 i another smnmdieant, methods foraedati.gas'taN prctes eenarnse 4inga an act iag coinimpand of 1hnum45: 1it RR16 wr cdpendentWt e7h r5 i ken cIy> aid Itn or a subtiutd ora nubt mod Aa, vrtaky Lk La andiLnare, a oS sSunintegr frm ) ao 5 -h ivM ari~ tO~, UNXy4C:avc the~ amwdr o.Fbma,, m Jn ither ombd m of Rhmada 75 ond th L~,t~ 4 L~, ~i 'i>on~. C R at sapkm of QXmiO-a 75 aW attendana dritiotato iaR-, -in ait h ~ar cdiiannu. ihe xuthodc o a compowid &4 formala 75to the sendnt d~nitons heris tIT(CIGI n a Surl-tit.'the'mbodiment ~iniods covrs a (ompound f fem 7atA the a*tedant dec as wherrin is t 1httyl ka.a fittUttr enrbdime &" rhes onri'a enppamd of fa ieda75 and theC itdnt dinidens whtaRs2Ii s C0)O h La a rra ebodiinor the :mthods ~Cmd a rp_ of fonda t and the~ attendanx defanaons wh4 a a i(0)Oatv como a~~ cuha w d~ ~ ~ wh .as aTaonvI Wm SAWtb waninvl nnad ia~tod xq~pes a =WOM xfi rntil '75 1dt aOetaan WOV wiavern R is 04t10A spo Rj in Wdndya&Q in a t~u=%her s Meruhos wsh a wmom ofn~ tWtbm~I 7$5~ fmir' anb&o(dan- tha "zad mub at~t vap fQa 75 ntjW in .a Itt~en~n ia abd ownpsz A ccnpand ofdnumda 75 and tw &m-..al k. It Q! Wwso sot R >)l to 111ra tj is stl O VWI sOu" . JI atV'"? ~ ta; n~t a V~NuPaand nI' fd n 75 XMITd is:.evy R~tV 's t' C> 11"GM R, t1 (aj YR 5 a a krnhun P. Ae . hodsRn a of undI aWR i JQd . .R, s Awl)Mo 0Ab a R In a further biment te irmlds cre a COMPud of amuan 75 awl th trndn dfionAs wheriA Ro in 0+bAyt R 1 iA t-buy, i 0+buAy R; ibut R. ia KW)Ore a C e s is and <i7N In a fId er embotiment, the mah3a Komprise at comtmd Q oflPUOsi 75 ad t ad ait deiiio . whrin R ia 0+binyLi isyt It 4r ist 0+butyl is It-bty4 R a C(o$)O'en Ps C(O)OMe, t is Nt j isO & e O is NsM and is In anther4r emobdiment :oa for ar: ating a s ifttin prtei cmrie an ClRain Compand W oml 6 wabsrrd z: o a.sahitd oasus nd rkh aea it Rt and 1K are bydrxy zninoyano, alide Go thr, seram to sy i iohm, or a shosittd Mr unsatitutd My. arytkktr beternoyclyx'hetekt ~tyltrasyK ~. hete raodrybi; r A 1kakyt arS 1, m.nsacdride olgosxcac.haide(, tyca r' amratosy glymopyusnmy 5 t gle $est taguuoi -11-d 1 is a n a o 0 h fr ~n,, do ilan hd onpt c ond o r andni one atLad Intin xAeern iN f W imobr ~m denhf oadetson No~nd m fAnuen 6~ adtm tandamam ddotinit so on a a C s t&ne se ntoc cmnoa coopound f io o7 n tAPM 1d aw W-uee u dinini a~~~b tupvk>d ofanmd th hd oaiina~wiAt'rWA 76 :awl tWo vto~It i xosWhsri it is 4AiitWy.On ti aheles It in Re "I &-. 1 'uh R 's In a:iamar bozi tdn ~ ~ taa ronnd,':f ~ 76 SOd & Si rthar yrbodiengte ho s conrse a compound o' knalad and th attndaInt definitions hrei R ylIt is ethy in is i is is, vs is 0, au!d4 is 11i n aidkssnaredimegthe mehods comprise a c1mepoundl noo imula 7n d di stuXundantI defieicn-Ote w a R is ediiRs'A is it1K3 s Ho kis.Rialand R a nather ernhediewt, the mceds compaisea rr nsoo ie Ibna la andth at tndr defibiienos wherein R i etohy!, is hy! ,1" iP i t R;S is Ch R, is , Sind RKs is'reihyt In a' hlhr OWmboMa- meohn dompds a . cmopd a f'etmia 7od the attendant ' definniswhemRn R.is Mlt is eT!, o is g, s 9 H, so , s: Ks toya L is NwP In a finiher embod imniem am rthods compruse a compound of ft azida76 an the atendanditIOOSWherein R is ethyl, is rThy, a i Q R is P is 0tRj CU, is H 1$ a Id ntyf s yad ni is I. in andite tembiodimenL unethost f aeivsai. smrtninimitWr3ei ti npsn an a5t$i C>Xng lil cop it fanna 77 N R R 11 wherciindependetuigv for swh oeurente: to V a ns ace H. or a sidiUnard or unitutd alkytartaaiky a m and 13 no bydroxy, xnino, C7yana. hAn, ton ster, eaterad keton *ambOxylic ainr o.a 'o shbtf a xitutd or nd kyl ss atalk htecygevl y heerocyctytaikyt hetemrsryi or heterearhy; a itadkyl SOaii. moacchSande, ig~osacehdd glyofe -s 1ycyiopyt ghcur~onosyl r glut tid amd .LA ., anid t ar 4 NRa or n In a further enbodimentthe ahods caprise a npomuld at. 77 Sad m auLatie, a" when ,,,i \4nefud hereoimn t is meoscmrieacmoudo aad 7n. eena ena ihodlnant. RiC i l:O3 UsR~a ~ t.g ±7 ~ in arthe m anm trNe me&ods eoapaccsieomrd of romala ? ani the etndnt dAnnida Roman h is Oi in ahtrtne' emohnn he methods cnaprke a comaord of fusenula 7 and the aiht de lotions whoo.a it m1 :n afflser emnbodnnen.tIon methada vOMdse a asaO nd of MIa 77 and the attenaa deiRs he Ra Ois H i a fkhmr emnbodiman '' methods coprisesacompeunid of tbrmula 7 and the attndant derthOOt ion heoei Rgi ft hi. a writer emboediinti th ethnds eoniprise a tioinad at' ifonma 77 mnd the attant definiin wheaein Li ia S. in a farther embodiment, themethods cmposee a compound of kormnia 77and the attendant defiitons whenti 4. is Nit jt . farther embodiment the methods comprise a comamd of fomisfa 77 and the attendant definitions whereni is NH. in a tether mbadiment, the methods compse a compound of'kmna77and the attendant tehieona hen L is S kRfir ther embodiment, the methods comprise a nonond oflrmul 717 andthe attendant defnitmn vwherein R a ad R i In further embodimet the rthodse4ompdseaco nd of bnmaa 77 and Wne attendnat deftions heroes kmlis HH and 1:4 is OkI ddm camnranid n 3 d attendant de thsionts vhere i F R 4 is% HRh O~, arnd Reis tt Stt o5( defututkon wherrsin R 4 1, R £4 H Rs tl 0 .Ri is methy, ad Iis H. Ln a. tmher embodimert th mthod~ copi a comipoimAd of Iau 77 ad the 5enda dc4oE)a) werzti R i t i 01H R; A nat R; sn it snd R& is fl tidam detisams w i Ria H. Rs H R 4 0E methyL R is Il and R, 10 in ho hot ~ Lot &h NOB, ~z oldsis 10 som;s *S.~.rJ.77~ OWHI acaAn, or apu wwAlu i6n Wkl "SOJI ,he 4L. n andt 3? Ao (I KI w KiN t7"i flN 5NNu~ S) 5%la ;a b &O.Ahds nt poundf fona and kd ie K a aSbedituewn hadeimnn nOA cojo dsoua d the t a o dena~ett Sin... wbdet lSo nZmpd a 4ot ah adibi u a furter emoimento(, t mthods copise a compound of funnik '7$ amd t tina t aiitim whercito une ia i .n sN fl Ilmhtt' ambodnmea, t meatda' mprisy a ompeted of kammia 7$ and the attaa definion~ whfe b a S 0 ai Radl s Ia a Puther imaimtemtodse tempthet a compnd of ft oa 71 andl the tnou ddi &nsions whereinu m i t a A L> i Ra a ,dWis5 In oos nutbe emuixaento mhds fo :sttSim :a sidu proiten nmprti ting :mO ed!#ainggei5i~\n{ahR RS (R)n S S 0N'iOnO.dnIdey f a. n rin RIt " W and zaare hydroxyt amino "nyan hYaRi wier ste, 'a ikd Itn c rtn r -c!nixl:wv~ax, Oa mdahad dtuaid or n cita tekd alkyt. aryt ar9iky n haemaaydyf het mbgWiakyi.etrekary orte9 raamid; hIa alkyA, OM3H mn oacchadeN ohg 4 osacaddae glicofuJtatr sYl A ai alkone aknylene. or is kynyme a is aan iasr from {)to. 8 inRs v9a m .ia anisteg trm Q0 Wincain o an integer om to 6 inniabiv ann p a an iuea am C to 4 incudv In a ather =nbodiment, the mtods cntpnse a compound -Aof in t9 an. d the. attenadatinina wherein a is . in a further enbodanaat the nmthods comprise a camnpondt o anna and the atndant defin'ns whertiniR Ia Ot or anethyp ina twthtr ainm the mthods conrpris ca xtapoud eii n h at endant dean Eons wherein nii LaI n a ithercntimentthe m:,ods comprisea compoundoffanmuha 79 and the ob. a 9 , sdlhey V a finare ombodhmnt the ni thoda s opree a compoantio :trmda?9 and the .timdant de .aions wherein o iN I 'n a further embhodinira the m ends canprise a ompound of Vrnula 7 and the attendant de"nio aehrein p i st4O In a ater mbodimsent~ the nethods com puie a com~pcund of intan7and ahe attendant dc.fions where R is C~Ogi. h a fiuriher eniodierittheminthisespioea copond of fonuta 79 and the tvadaade'afnidos wherein A inknyae in act US I athe1eiedn went to compound a f famnda 7.9 al 6h .3eda idefils w in nf2 and . is OH or methyl in a ftber ebdinGet th Ums mps a & oma ad of fornnzaa 79 and tio dit R i M O a; t Ind i i in flkiher cmbodiment he( me"N4d ompS se areampoun .f fema n the% attendant definitcans wherein n is 2 Kis 01.ourmiethey, mns L and% K s methyL in a futher imnlaintent he mehods cnmpopsea compon of formwk 79 and the attendardefmitions wo n is2RKs or mranabm ra IKis methyand is 1 in a thee odient the amethds compnse a command of fmnnat9 and tKe ttendatn definitions whein n is A Ri OH or methyl m i KR is imeth c is Iand K is 0()h 1 i a f.inhrmadient the mhods compose a onmpotUnd of nda?9 and the cannan dfinnWhert& a is 2. R to ORo antys m is 1, Rz is methy~ist 1 eds '4(16) P1,and to i in x C(ah is i hy Cs1H iI further mbcdimenmthe methoda 'rmp"k a (oimand of tamda 7 and the atoedat. deibitlans smin n is R2 1 is OR or methy. am I .Reis mnethVK i id s IKei C(CH& i is an.R CO2andAishk ya In antherbenent doda (tinga 0 swi btkmpmoms ords andan R Re 80 whrerine pnly k " for Rgacdmry o kR 2 eA~ it t. t 3 ,R e and1 sw edistkc r~ oxyN aminO, cyao baide. ORn. dh' cstenaido kcone, taeboyic acidntro or asInbtatdrn bted alku aryg, nrskyl hL cclyl he rmcycPyhdkyA, heteroaryi. or hctet'oaralkyli 1m a oikd ;&f e o osscadadr wW igos it~ wi 1'4 ocsnhr toiennyresylv gloo svLyoigr od; t I O y and q! at Oth A/ar aay d n i''r a tated or anbedithd w skyn aatal.yt aah eycy Naeoesak heOtemary3aetrpraky Intfurther embod tandhe nieth ommoidea ondad o emis: Oand the t endanA defatinnon whee a Is C4t fefther embedtne i mtod enmpde a compmidf tnaLh 50 adthe attenmdanisinshrenR sC-~ tno furthremoimnte ehoscaps a campound of WWrIl 10 and th10 atnwidat dn itions whritn.Lk is Oi IIIa Atse b t eoi comprise a compoamd of formula SO oad the aadn defetions whINiSN L ismty i frthr mbodinrar, .he meod coM a"r a omponrd ottou 80 and the attnd3at dw-.iden whninh i O ,',xnnc a,, thrin em~bodib mhods comp',se a compoundafmuaDanth atenan deduinO 4$~sraetin is OH. o further embodihua the athodcms comnpon.d of Roniwa SO and he attendnt dendon waeN14i l atedaafnttxniondwhrnai as OH. hn atthar mbt dimttnhocdlr conmpris a' c 4 ound oftfrmmla 80 and the -adnat deunitions w~he t is &Ot 0 A ~ F:j~s jadm~.S..to Umoods Cuinpoac * :rwnp aind of fbmyam K) Si and "be 5~~~~~~~~~ ",i4.~l 0dot tro hCtlLaiO I tii n h' mh crise a omtrd oflamada 80 awi the attenldat denrf~fstinhrent Ruo ms~ethyl. In afurther embodimentthe methods ampiso a c o l o f noia 50 end -he ~tndant delfieS o wenL; is C1 hi a furhenbodinen heamethods ense a compound of femmda S0 mndhe amendaint defi tions wherein is iS ha a furthat em thods )ompast a compound f fen a SO and the attnat deinitions whrsrotiRis OHsaR 1 iCh(] Ic a Ji vieewbeenethe miethds ongse a compound o hmlana 8 and the atendand ecansa whaenaa R i d14 i Cis 0 W lin aichrien' r~nbcxt~nn o thm eds canNsc a rpco aca of nos and the aSherdkn itt0R Wh is OU V$ k"hf$90 C-"'l N LRa U 0% sit(enn adiihconn wt eeI R OH R s CU eGH R is('I auntas R$<is t+Atnd ia Athhr cun edimen a m~ ie sthoa c ic a compounrd af fotnda SO andtet a anct delantfions hain R is H 5 Ris OI RR bin methyt 0nd is i, s 01. U)i 14a:40' enaximndt- cotods COmpdse1 at comnpouend of thormuidn SOnd the stted de< findions whercie Rt is OH. Ris CIYOH Rt is 01H Rt is meothyi. Rus OH.K and it is OR Ira a .htlear esbdmr temt s campuses a cn~opound of fonamia S0 andl the attendant dedtnis4on) whereO. lisnOH isa C>hO Rds aH 1 e ethyl it. Pa(d.R iHt snda-isOK11 i a tedher embodimenas tie metdlods eampda aopoud 01ficmaniaS andr the atternnt dctfihions wherein R is OH. H is CitOd Re. is (DI. H is nthybv Rt s OIHRa a GH RO O dRs In Of futhe edinen. te mehods ompse a compound of ).naHa f) and the is OHL iv la vis O ILO end R 5 is 01K ia a fWthemabadsmetunnt, the mehd upseacmom f femmiaub 80" ae the nNvR -s R7 As Coy P4 methyk H R In amods compe pod of AmnDA so and he atendani dititans whomein Ri OH is MYOi R, s R2 is me.hyi iOfas 5 OH~i. 4is R" a 1is OH,, is n Qe n is methyals 0 n a father embdiment the nethds comprise a anmondd wf fHdaa 80 and te atrensntdflit|ors Whiereirt Ri 0 HR is C O0, K, is 9MA it is rnslhyt A is 0Th t -dMM~ hymn"". a O 4 is O~~~his On R is: 14Ri eh adLa n a either embineth, dm lehod' czomaprise pond fika 8da 1' and tr attendant deflnitions whreremin R(Mt Rt is CIBUH 16, i'OH, R, is :mitR4 is OR, Ri r aI K, Ra di, Ort is (H Ra Is OH, Rsaof is ,I0. and ia d in maofhher embodciment se etdrwi aonvt~e a cannt .in nida20cm us e wh .ideednl fo cas ccanence.R~i iriy R~ sOH i R , 'i 14 R an Rsi are is Ofj a s ntdd itr ins.bQdated 0,y ah is k. }I a nothr .emodmetti methods compvus' a co nnd of s founhi ath enan dfiitan viein4 sL In a frtherarie 1 nti miedds comphse atszmpound offan4, agend the ahndant definitions whereink Si H In a Anier embodhsienthsmeiod mi a ampOCtd tfia:da S1 awl d the atendan deinzions whenednihis ft Sn a tthe~r Kembodimant t~ i i eahor empa a nompond of forla8 od ie tandant definikois wherein L is S1 hn feiher smbadimenst t mkthods ompisea comnpound fat mds81. nd iha aasnsm defitions wherein n e In a nthe embdiMY simtoswopQacmon Rf fo dn do, attenant ddinsnsa wherein 1 inae-4, boen thi mnethods aompisa dapm ffrala p I 4 ad h sadat deitionihnehetala l'is H ando > Ri si. in afirthttr endaniennitheIt )abhas to 05nprisa a comipnd cafornmu1 SI ad fis tant diidOns w ;rin R is Ha is I & and R d h T In a HUt dinir the nsethod comprise a aonpannd 3f sixa& PC a ds atendant dafinidons whArin Ri is R1 is RisRsis 1 and 'Rl, SeI hi feathar embodinsm, tha sahds eumpris a Aolplsd of itiand lisa attndant desdiens whemrin Hia 14 R i~s E. ih is hi. teis H, anis~ Stnd.is1 in it futhe b dianennt the etahods comprite a compound fisa san is atainddniinas wvsint R4 KU Ri s d, H Reis~ H 's St. is 1,audi In ansatsciemlodlnivnt. saethads tar aedvadngp, a. sittiSSnaktni 05p5lSti~tng >55 ativadng tinmsxsssd affo nndssU$ (k 42 heeh ideenedyfo ey ionr\ $5 et, Jo to ea S W nis~ ani hma hwl t v; v 4 I a y; V'than s M~obr scra~dkt o letv Avhm A c.r o r >-2 to! b" u saam! V is J.
3 ao- hn sad rn V 0 or a mo on kn0t auv2n and is n r HOLM {) an whod; LA td~t flh~st&~'ffR ~ (~i5 ~ At ot vidof Urwda $2 and h-to a fladhetmbdiiee de m~ethods comprise compund of' annada iand e Made d nist warcin n i 1 R isa MR ow a and R is C i(. sue idani detht iOOan,<fr4:M*Y a -' I ' a 4 Rg s NNh (X)gig and L is $Ch. ina farnt ebdlina ; he meaffiods omprise a compoad ef famuda 2 and the silnant td eaonihe na n is I *i i Cl. 1 1 Is liiy. i CC. IL is SQ~. and im s 1 inanth nbd nt- etid for actieunn a slettan pnsa. mri~~~sxsing an acavating compound of fbnnuta S3 ll'nT RR NR I3 vwheretndadependantl li each Ltskuten. R and R;a H hydxy, amlinoyan ha4ENe O 4 other, ader amiido ketoneestbxyte cid a, or shaituted So ans nd.d alkyl, aryk aaikyl, heterocyclyt I terocyzi ' k heatarrx emra yt ela .y-80l mnsitcarde &ligowacehatide, glyceiuranonsyl genopyanosy.aNon OsPyKo gNUcmMed; and nand m amiagen 0 h 0a a AtnuembdimeniPthel ~inod cpse acompund nfunna ez tad inc anodant dera oes wherein .osi kn ftrd c p eaompotund f l n attendi e ina itions 'hrein R i hyeay and 5dhydraxy hisa fuiher ernbadin4hde othods emapris. a c mposiei of forul 83 and hie atiadant defmuens wherein Riisi In a fnrt sbor eimdi z, the mewhods comprise a comrpounS. d ermika 83 ana aenant delntionm wherein R is Ki stadt definior aeenie ha e re aapw ~ntnao a ander enaieeh ads anda copom of Tita 83 andi titktna~~ moarinrn"ai hn a further Ito o i a com:910o l attendant defitins whin . Ri is 4hydroxy, la a fther emnbodhnent, the thnods aompris a opoamd or 83 and the atkndaz4 deat ica wherein 1% ia 4,dhox. li. a .deer embodinmnt, the mthoda comprise a conpoad of' tormoda i83 and dm ~atonrnt nions whrAmn v iS R. s yproxy and 5-hydray. M lP a boe mbodimm, thS co a compnad of ionda 83 and the da. i sw iai, R S 3-bydroxy 1n i- ydroyi Ta R an i uR 4 In i fothr embodimtt PAhe method comprse a ck o poofilMuu 83 nod th dat ddnitons whint in la 21 Rt is 3T-ydMY and 5-hyavy Risa H. nR is ad i a anvwxe oadimnt. ht d m rnesod a c omp t'e{ p$'txna 53 e gdnsung 6615103n, 10"TW to vt 2- R2 in tyday and 5-hydhry. R, is H. 14 in to In n i 2.8.3-htX~wtand ~tydrry, R,, i UK it. tI i and sn4 4yn I inu ampf AM= oommis4 attenddzn icv Wftavdm nw~ is 2, Rin ThYA aund R.0, i., ln I Q R4 estngniodtRa, cfbery"; 16cIQt or aSubstaied orunabstiutd alkyL aryk is r ;an NY a or asubstituted 1rnusne iy arydkaanikyl haemcycl-yl n a uearmbodmentde mthos comprise, aowaud of f'oruna84 an-df in a her m oien the method,, copi a onwuddina 4 an~d th-e atentmde nin wheri RQ in OR In a fuDeamboima theA' ehods em8ris a opudonnd d the, In free eboimetde mdhdscompdsew a compoqxund oaf fannula 84 ad !he In aAuthr ebodhastthe ethostoigrie nmpand o fbrmia84 and the atdantd o hmRe is CH a furhe embod Rimt t>he mefads comprise a cmpondf femmaK2 andx~t zthe b naant ~ definidansZwhomint a ZOQ antd~r audiok . iha mtod cmpt~ a eipeod Yinmt2a anIe datt upa d M y datrait R i W, OFT h udha SlN a t a A ia cal body wuo n a a o pnv'xd Hf' wu dea dodes a R Rch" amd Ri 0O .siandamf >nna ",um i Rt R o ait is ON. d fibd liNef n ti d iha4St \ aa lipais 84d K Mtus at tdoaiUSR;5 wh eol K; v R COH R, A Lot K, Q ,n 'nadaat de hins heeinI is R11 & Oit iM WA Ln K is OHd 'N d i a d"' ae it a .hmrar cmbdint han dv snse ~ompnd "ffemng nea as~tndas dN iindm W a Rs OH Rei Oil t s 01 2 Hi K 5 is (A it isH:31, az an atn tatpoe m enth 5a sax5 ~ 5 4apU 3 ani n.t aaC~n fR(4 sanau dhi a waak 0Ot.saC1~SI 5 sOWi~ s(A tsi Oft r4 Cindpe0n11.arnerec R, Rz and R2 ame ,hydroxy. aminwi eya ide. dR) ether 4 esteatmtd ketono, izboxyvik asP ora a subtitted or usbtituted a~y ar. ~.I, ky egeoy heimmydyial & harv1sy orhet'.'vrelkyan Rt2is alkcyL 80/SCL mloo hanid.lgasca 4deeycofranosyi. yicopraosyt I g nea oser ginnmee . a twh Thodie n the isethods conprise a Componad of fnhand! v$ and the mvndanrt deftionrav herein RA COzMi ina itenrnt~ennhe ithds compise aemapovmao fan a hh and th atnodat de as wherein Rks ethyt. Ititi~hor inmbodinmesa the mesthods comprise a Nmpoud of: fonuta d an teem at"tUna definitionu wherein I is NeCi pyaltidine it a further embodinant the methods compose a compound of frtmia l5 and the atendandno w i A andR is ebyi in a fuhhr embodihnmn the methods comapise acopwd of tfnnisa&t and the tiend tdiis wherein RUi COtRH and Rhis N pmisin ha a fudbter embodiant the e odsde omfpise a mpounN 'oSuis m5 and he adanotdcfintisn horeii is ethyl aud Ha is Nai'pyrrolidine in ad Ther enthodinem4nthe mrethtodse oprise a ompoundi of :oanmul &5 and the teda wridosperem. P isCg kAtRa 4 .eiatSU) enhy and<~ RiMfylidine. senother eatxnivmntho'ds for acdvating a sirdin pmteela coemnda usmhm n achivai ny. cmopotnd of franuda y L 5
L
5 86 whe indp yfor tacit Octevnce X, R/. R,, gR, R R, aog unn R, hiroy a'inv cyat uhdk kOR ether, c~s~tn a n vt£)nugebariteh W acidn on ubs ted or azub&itted alki, aryl s::rjk"y'j hc~ietrecvdiyebhete'rocxdylakyth'Y hete'y1 orhek yyrantsykgh 'ayoor md a and0,ar Ci.C N1% o* Sa.d y is I or a sbtatled or blttcd r a teocyd halhrcy, or~ theaaly in a ndthorK mb:d l. the neods conpadc a.co*mpdi2 oZf f ia 86 and the satant diewh.enin R is CL ia a trcr ;eh ,lmimds omnpdsc a nond Ott and o In a tatnr mbodinsautthe omhods comprise a ampound afdisnSt so and di admit~ tetntsundveRis 011, hi a fth r einbodiments the malaodsa comprise a comp ond offtomadla So ad the etena, d 4 ndo wh ean is .N(kkh 2 Ta Anth 2do dimon' he methods conmpuse a mpound aff ida S6 and The l k a i embodimenth mrwods compose a compound offauiak and the attend Nt 5rtiowherein~i C(0)Nt~ In a furtler embodhunen ins med ada ConMPdSe aRapond WAc 16 and dwl endanw! ioa)mn i H h, a furnereambdane the methods 6or a Compound of foml 26 and dhe ausadant d(lnatrwherean T(e is OH. a0i ftihdarganb oiient the inethd .noa"mpaie a sentptandof fe aa t and thn aerldaot dfitions wherein Aisil 01. in another e2IRbodoauen~toe odioacomprise a copond efftormua ito and0h sttendaut denaltions whereinQ is C3. ia ftiher emeoae hdemdse a ceopound of f onda Sd aod tie attendandethiions whnnaLis O1) tUtA dn key Whash R I C n an d n n s . cile t at dd 'iois wherin 1 t it IT lv' Its isf: N'P IAa :fedhs bnh d ilk a teads nrdse it p n tna $d dail t~atdia eaiene he 2IdhOfcmp< opond ads .4 si sh iiAhna i PCRsG 01,k ~ I is SandItN in a embudoadir thex ihnt ompfa mpeed Of iNawsd dlh tda defiitkms when a lR is O~L 1 is N(MteT is C IA, Ra I C(0hh Ind OR R Uts NOL R a C Sa .th e $mtdiment. the maeods comprise a <4clmmnf n 6n andt definitive w "hra it is N0Me", R. is N1 R Q&&s Ni. is Ot Ro I a OR% A i liC IA a further nemodiment, the methods copise a compond of feinma 86 and the nda dnitins wherein V is CIL in O 13, Ry is N(Me R is 01H. RP CO)N R tot .is cm, 0"i1O , is 'H, Ld, Ia a .tathe embodinreznt, themhos cmp rise a comaJd of fComadjt 86 and the zindsrnt detious wherein F P C and R Ci ROM.Ntet t SltI s(Nt~t anddL Rhie 1t Mt an RAn51 da W rterk F; is H i!i s t U opr RA inu~ 11blf ThytruA it, is ~ 04 kn twtZ'x c~nOditeat the iledt~As )f0flf OI.' O 4 l ~atnardenretvs' 'wheVein R i H, R! N0, it k is NiMek & OH, Ad (D)NH t a Nrther amdent, the mhods compnse a Campcund offom 6ad ,,kntis dtsities \eraa 1R N is n1,i Me iN OH Ri f(O)N R Na a furde ndtmsnt the methods comprise a eompar of maa an isend, and on w MP l1 a furta embdienhe methods comprise t compaud &finntui 86 and he tndtwa deiiin wiascn s H R, is OH, R2 H NMe%. R<s 1a OP RisC)NR is On0 1s is Cnd t is O, inathre'odmnt, he reeto aprse a copon -~rmb N6w the mstefna' dets ns wheren R is H R 1 4 W k is N"Me 1 R A isQ Rt(Q)hWI , Is R .1 is OH a i t is C to id in amotsher emboadint, ne rtho ds o c iva ea a ati d t4'rn rprise aSa ani. R W A KttCIL At (5~3Nf( M, x; in ) OI is Hlo to :(44 is AR go i is COhTC in vonve Onhaimn SonomI( b ad or A~. *tNi1 - I .snnst e~ia-' ~i nR s K (II Ri iM~ i tx.k SU ii.i R7 Rma i R; Or a bi Ua bilky r, kyhry heteocylylsky, htemary4, or hetemanrdys; R;is aMy, -S~hT, motlanchan'de, ga chaiegy fau y, hypyacy Lu yC £, 0, o u ie; and andi math ar v e funhO ehadhnor Ow methods con d s, a compoevn udc It 'a dfttar csnotat~~~~~ f cna ?mo It . fimt bod lox tho rnhods compd4 mnd it rdaluiz and i t att~dhni ditmi imins y and it, in smeh lob tb ermbdiman &tehnda campoe a e a d onoa atand att Zin dofiaio riln I' T'e Ianneiniden de>Wn4'tn NAv\ oeih 0pLsa QO potottnua 7ii t Jona bnther emibod ntnt the mathods omprise a eomn rm afoi Mott 8 andi the -dan dfidAt s Wh Mi R A y RIt is ntadi s CQR: h yt 1K: andg % inaa thxther en1 hteuut. the methods~ tampuse a ro nn efhmla 87and ehndntderdoneivdnessme "Ny sa m~ethy .cage~ Vd V"%'c K' is AOvNd A proTes'ed canpaam4 o ;-Iunwda 74 is DgNgdAtia pefoni eon pand of femadna 12 i~ Hinukkit.a pr red emtaaad f fhnwsdaUio L(+>Tzgotliloneie; a ufcnred oempnerd of Amf la 19 i Caffeic Aid Puo Etera pr -TNed napond of % nna 20 k Rin ied a pmemd COmpofnd offortd is BED ($t1p11anary Sao hn Cmged aet phnrmorcedlv~ acceptable. adidition elols dCOmoplexasOf the daurnoesdvadag ceopounda deacriin hereni case* werein the cempounds maty bave onx or more "hird nent rm pi e mgm may be in cases in ich the sirtainnactivating coponas have unsatuataldcadbon-a arso dudbieendt bt the dia (Z) and tsan (E) nemare enotmpatd hereo hI unes whuaen dth compmandomay e Romt n iwnAmede mon suek as keiczoen tanten. audne O CR' an ach tmfnt rii i c'tejpiatedi as heng~ newid whinb the meathoda presented neten whether e 011g in equilib an or linked in oe itum by apprpriate aubstintiron whh .R. The. mIiCaing of ay suaitne t tny one' occute is ndend t o ' mrVn.g or an Ohr adinenfs nean at ather snonanee sAe iinded in th~e methods pvosetsd herein are iuta ot' he irksvoativfogn codindes &crtbe hcreb Pedrugs e considered oIae any covarntly bonded carriers thad rlease he antiv parentorg in vivo. Neraboites, uch as in vivo dgradon prova of the emrpommda describedtherein ar aloe inchided. An ag- and d-I-awe of the abve ""t.i e an nod descdbed herein con also be used r activatig a member : ta. shinin roe fiamiiy For exampL derdyatmves or tandogs may unlte the compnnds more stabl er onproe dr abilit to trave-re cell mirranes or being phaguetsed orpnroeytosed Exeawtry dlrivauea wndade py yltd tdec.nedadesuibtd, es .in 9.S, Patent 5d( fon reverattri (Mhe~r dedvadves of nunveraamo ncadude es and tran&aneveratroi andI retnjgates thereof 5$ w act inal zsut a: r a cside (ee, eg UKh Patett 6,n 1 us hpd t to picekd or exai 3Y 'ha.D-.h coyraomde, ca alan be Shosari talax Bochemical i. .pbise on4 .6 as BJ0314Ohrdrvtvso denae 40 IN axkts$2Ae2. RaeakotA ad dennvika :tefntadoN4t~ prpaed as derbed in the et mg in US. paens (I4,037; 6,361,.3; 6,270.710; 72,182; and lrndolini t at (20{02) Agri. Foo. hem.5747. D'erivativea of y y sae dKribe, eg US. pant 4;$1.( Rvetucl and atba avin com~pondak eCan WO he Obeiaind coedaly e A 'mSm in Geana*tan salimn r . s Mv4 tocm3 ail it ENlv 1)Ce a' haast patially aold trrom its ntua envijronet prt* tuuse, ier e <anple aplt polyphemanuty is tlated fnmi ~ ta. mind Parkly or sgn caty puded prin. to v nthe metods described h01eret An acivating compound may also be prepared syntheiltaflvy i whib. me i would be free of oitur eomptounds wSl which it is01 ual asoiatd, n olustrative snmbodiment, an acctivean compso compnes, or an an socatged with tes than ab on 0% % % to, O." pS' Ar, "O of a comnpoumd Wth W"c it is ratsurally a:nummtd. In cetam tmdients, a ettnin hiological timetkn:m n~y, reducing bedy wegt i.s moduised by sny ore of :a shu avin; compood or i ens of compnnds (op having ionnui i. with thepm t h . .h g. u do>. es no mhoeorueson compounds For exampit cnsb embOmns, a 04rn5 c.r-t n .olapnun1 may s be ay copoud trat is capable of Wnrasidng Qh ee feprsinudo activiW y o u wnht p that ;he compoun is ot serat ao lvoz r anSly Ta 0 e a~mpthd pebt~ ched #sa in .rA~ te C i~n dt this 3 chome io S mnn , asirtuin-acvtig Cumpound ay be a compound 61 Wy one of formlas -,I 2347 $2 and 5487 with the provis: that the compound is not rasreratrolt a flavone ox or .y of the other compound ecifitty ca d itcrei< arty Other' comipzourd which has heen showin to love so. ac vating effiet etn a miinn prteini pris oibeprirydat ofih 0 : Sapphcaion In anex paremdmna ii sottatig coweomnd See to i x oaf ax. vonmrgak 455 in Lii.Sfnest. N 6t 4OA5% or 6t245he daosm ofwvitare heroby taco ate byrierie c thi enr Fr em in emodimac a con ;ivitag mpoed doos ot inchide a eoryaun haing5f 'mo n 2a t frdbdow: A is ckted hvnn the gaiup ivw'-istng cf a \rwb' d raind a double brawd in ants K vi s~eleted iftom the group consisting of O Csikcxy, 0KK tand setdhm The gup fndstig f k ' "',d cc. a y Sa sefe am the, o- g-uT On 'i &' alkyl, O e'I atkencyt W atkynyb '~ ad cnikaky Woma' oeaoe frnt grou i and Che Upqy '.ar clse o #a oupcntsting of U, CitQ alky oxr.. dkOa. Cend CCOdv isSETvwvan:o isk; ha d s y cinm !aby W, Ri s adw hd frotm the gaer consistig of R C% koxy, COD and A.CO'rAk 'iLN3 and a her-ya en t olny i t- and CUii syo&yti rmtesrnpO~~~f& ft"P ke - 3 nembdanen the a ECtSOnAn act a. ors unh S aivmaictkm cot have any ubtohaladabidly to inidi I iiAe ith lsotdua se dkiAh inhib ivosine protein kiasses at concentnaions (egK:. in vivd) etfediv fir sciivating thde descevgase activity of the sdrtin, e g 5 SWRTL For instance, in prefenmed emnbodimnts hfsstnu ~i.- ssivator is chosen to ha''.ve an s$.'.'. 5'r aanJ n sit1uin desc etylase :ac's"ty teiast 5t fold less~ than the EdCSr for inhibi-on of one or more of aktdorednetae andt/or tyrosine protein kinses& nd even* '.som. prieA 5 5 . atSh leat toidd% Plld seven 1()(Q k 1 N~ju ebcad fogasst~ayth.<g Kud msc autitv aide redctse .edVuPj and tynx . kina3e activity are wi knoa hauil.: th dAns to peTrrm sr4 chs d assys ti bd m. "an W,. pmwwm atgy kinase says ; Patent blicaton No 2ON0 4 7 fr d edt asay tyzsine kiae assy hits may Nbe purchiase4dr y fr.om Pom (Madison. Whoi world wiZe wo c prcnegaatn} nvhetrogenz (CcAdbab CA~ wedd widk we layovegeoas or Molesue r Devices (Stunnyvale. A; wodd wide web a mokku-rdeicesivo) in certaint e .. badh"'ntt he cbdi naun aotvatorc do not have any sbautil ability to e~: adie ECINR irdie kinwte aftivity at on entratiors (txg. i t ) elinctiv 1 for activatinAg e dacetylse activity o the inta. r instauc in prflSmd mbisents she astci avto~r ehusen to have an W050 fbr activatiog das set activity fet is at least 5 fMd less than 6he E 0&w fin dradng EGFR yt~hy, tand env taa prehab;g a',tJest t i \ fNd 1\MS fo anne1000 oess. Methods fbr assayig sactivation oCE(G tyrsionena active ax wed knownain the anecc e g a at. Nat Md. i: 89 (2(2) and Vasat a.Caceer Rsearchd: 3 60 { $ V t (2tXK0) dn ~the det Ws ac &atr d ont havcany MGM abitv cause coronary *dinao. atooncert ration (emv In vtlective. for acting the dacetylhase activity of the 4rtu. Pe instance, inrefryred embodiments the dertin sttin s chosen to hav an EC50 for acdvatiog sirtvtia desvis saiti tha isa d0fr Ahon and kwvenor ,i pvnrably a lt. la klIN d to0ld or e-ven 1000 fold hrsx Methods for as vv ingasodikaton are wail known in hartsee g U;S. patnipublcation No 2004/023150, In ertain e0bdetsh she t yl tin activators do not have any bstanIdal spasmolytic activity a;acaeentrations (es..ia vivo)effectie ha avaridite dice 'tylaso activity of the sittaint or instanori pratred erinhadnt the sirtn icativator .r chasma o have n EC50 r t ivanag ttan den+Vw. activthat is at east 5 fd es thaen the £CMI for spaamelyt.e sietezt (snh ason asrorntesanial msce ist maid praferablv at least a fld, R00 thk or even1000 W d -as MSehods fOr assaying spamoi ti activity are wen known in fle ar-T ag sP Patent Pbliation No 2OtW024S987 20=2090 abiliy tahbit .pai ny tm 450 BI (CYP) at cnenrlism ( in j vo) , ft nor tcuating in , eacetyiase acrivfy o thi esrum2Pt r msta nce prefe'rra nmbdimnts the situun activatr is chtosen to havec an EZCS ior iictivating sirtin (~See- s* W love too. (J2113,W, ad etyias acti-ity that. isa4,a l less tra the i C 0 todu iin. ofetP450 t on snsayn carm 450 atiety are well known in the art and kits to3 pe'fo su asayvs may be puzhased con rcialiy &ce e~g UKX Patnem Nos, 612043 an 61533,428 and Protnega (Mad k m \n, WV 1; wn wie web A p romeg, m), in cen amodments, t u 't Soiti act vatos do not hove vy 1u1,01 ability to indb. nclear factokappaH (shB) l Cu41 ta (. vivo) efliv ir ne-vatn the dearmylay anvtVy of the.oiorin. SWor nS-tace, i l nbc4.d rntid tno s irinr1 S.oti\' i 4 choS~j *sy 'i~" 'Rq CL 10 c 'Aitg it desrtolsn an-ili tha is et jenst S to1d lens- tan the 4C504 Ro it 1ib if NO' :S. and even Ay of Nin 10 itd 100 fokd or even -000 44l iess. Mehos fon away~ing Nitn activity are well known fi the art -and kits to prfonm suc ssy myb purchazsedl ommrcially (o-<g, .fomn Oxford Btimedkica Rsarc (Anm A-tor, Mi; world wide -web a cxfordbiormedtcom). K N>', 1Wo tob3n ctain bodimewnts the subiect situin activactors do noA haeanyvsubstantedk bihIie tomhibit-a histone desy ( DIOA v) class i, a HDAC citys 11. o HDAts I and iLa enaons (e. n vhi H v e a t o trn ctivVi a the tIanctyase nsvtyn of the siritin, Sc atenWco in prfee mn nto a 4.05 for activating, sir'nin raetyhas ac!.vi ty that Os a toast 5 nld~ ton tan the 14(C0 1or inbibitdk u an h'AC I ak/or ID . ind *ven mnre pref0rabMy t l:as W& ( okd, toN or even 100 OCT d less Mcehod tor assa HDAC I and/or RDAC I thrity are well known ihe a1 ad kits to per n such asay ay be Son ejm BReide "r Inc. (i-ain ~ View, (A; world wvide we t ivsino) andt Th~omras S i (Swede ro N; word wide web at taecm in Cit ith-odicanc'ithe1w Subjntt 4110119etwtiri dto not have any Rabsttib ability to acdvate SIRTI orchoas in lower oukaryoten par cur yeZa5 o humn tatogosem: tcorit. ation' -c., m siA flaeti o tat I he andvia c itt htoe an' ECO itt acivatny humn S1 dacetyiasc activity fb-nt is at least m told es than the 0750 r activating yeat Sir2 -uh as d S UV4va4, r(4 ev mn' potrably Alst mad fokr 1,0 0) tod or even 1000 Thd bcs in certain mbodimets, thn iatuin activtai copud ay have tho ability to c vaeone or more airiuin protein .hmoog su~ch as. for amplek one or more of baumm T~ $1SRT. sTRT, LSTRWT4, SmTS, SIRT, or SRT. in othe mbdinms , a SIRT aivator dons ot hav o, subsiata shiny to antvate oer sMwn paOtein homalogs. zlen at. for tpa. on o~r moe of hanV o SIRT. SIRT3, SLRT4 SIR'5, S T, or S nT ct cesratos (es. in vivu) ef'itryive fo nativadng tae demyss ativity of hua S'ARZTT, For ingcoe the 3STRT1 ctvrator nay ne roosn to have n EC5t iN a n Imman $IRT I. d tke activity foot is aw S is5 anky he Qa the C50 a- k aci tn ootr more of hunon S'RT2, SIRT , STRT4 1 STRT5, SIRT6, or SIRT. and evetnmorj pribly at Rt 0 kid. T00 hd o v 00old loss, in rt ain bdmnn SUT ad SIRT4modlators may be und to modnuzs lWd mobizinu Fo- example, SBRT3 ad/or SIRT4 activers ma be te to induc Fk obligation and my ho umd to treat, e esity a u resistance diorer, in other emodiments, the arui eot sitxuin <ctvatotd not hrave any nuon antlas ability to inht rrotein rina' to phi vlite riltaen aUtOd promin (MAP ittoses; to inhiit the cataWyue or trnspnnti actvitynN a CI 2, to iaaubit nitr oitd synthrase N ) oO loita p e adhs to type' o rollagen at conen traiu av 0... in vivo 'fitv far an atn i deceyan mn r'vyo zt ir.n I ot illsonla to rll refrtd emodihmini the Mirta]. bttrvkr t d ese to ve an EC5) r actvwQ siano d dlase adivity Rha gl 5 JM s as the I'5 tbr perfbrmning any of OneS activititO ami 0van mart" 'rderab a e 1 0 i!, 100fd or even *0% told les'ehdQrmaigptin kinas act, cylA xgeas ntivay, niti nxide oyamhaa~ activity, nd platelet adihenin V'sv5y ' e kneori th n andts toprtrm such assays may be purase co rcialy (Madiin 'WV' wrid wide wbArt pormeatcom)}, inviiamgen (Crtsad3 CiA; wotld wide wrar Devic S iyvasL, CA; world wide aits at o dc1vicesncomn1 or Assay DesipIs (Ann Abor, ME: worid wide web at i o potein iMeacn away kas; Amrdam iosances (Pectaway, NS: world vne webn amahmhicernrcom) no ccow vyctare MIv kis; Am mam Bioshiee (Pisaoataway, NJ: wcrid wide wat ma mmersh Anocienac.co) and R& Ssvtems (M in uio MvN; ui iwba rndsystemIVcum) for nitne~ oxide sytia assa kit; ondniS. tent Nos $ iZLe;Q~A 6 >4 2 Qand 6?747 kr planet adherion combinatutwith other mudpn.amd. The other compounds may bother dhtin and/o MJPX tdvator. For example Longevinex whih is a red whe Mtratand r ni ar ddsitin to reavarindtth tt atanr stytrsah quretn, L a partduidry ptu agta for otiijntin Lagene eon he obhainedt on the worddwide web at www.onevinsecon a,." p5~" A snwen ma so include dgs im,-- crmtpO,7nkads dir In en empare in ent sitnnttivaldng c oimany be ad astred as a ambin an thrapny &r ernple for sducing weightprvening weight gaii; or ramntor prewetdan of ehAsttg one or more snrnactivating compounds may he used tn cstotuoatokawth the itniowong "ortiabesity agnrtst pthenywpropanoianna ephedine. etsvtdrtcpheddrno, phentedrrroo a ehdkcvstokidnhu trat ago moneanine rerptake inhibi tooth as sibten My, Agayat r t, ;a ntaerg agent ( isuc as defafhraneor fanftThranine a doparriie agOnist (sudh as trromngiprw a medancygfstriaatg harnnones recepjor a'gonist or naee aa .me i scsi tin Aeti a hormroe analg, a "atuha rvu'l 'iertrr a onieit, a nerl e neentrtiong hormone anagonist the CD protein (epdn a eptin analog a beptin receptors agouisa galanb aitoist om a *si Eigae ihiui 0 orerer (such as odlirta4 Other zrrorctic agents include bombesrn agardt' dehwdm~Aandrostemnre or arnalogs thereot ghucocardcoid oceptor agornsts and antagonists aresit reetor antagonst ti ocottin WIAngt sntirvstag nisn.si toe gtuctono!hke cpfidp igeptor surh as E3umdi and dciary tauit pin te crah auion Altrrauaine one or nron sea edeivating connxaonds ay be usad in codaat ~h the foi~nrg.C at~ia(st agent2 tn.l alkise rednqs ' 'wadtsa, i gyOgen rhuasphorylu abeastho eyoease inhibito a poio oae ro tem in :tw phosphateso U inhibitor, a dipeptid protase inhibitor intun (including orally bioavadinble insulin preparatios) an isi imenting mottormn, acab a pernionmo plasfranto aavAted reepto-y Oi anuch arogisazonkS roseg hazone, pieghtazon or G -1929, a sulfang' t rea gIpde gi'naideor cidopropamide wherein the amounts of the first and secnd compounds reuin a thapeutic ethe. Other an a PPAR tdy dust agub a megi dand an oP inubitor t an embodimu a{ antidia sat amy be a dipePiy opda V V ox DPP 1V nhir uh a xor ol LAiF37 Way Nowartis N VP DPP78 UNj2I frm ort (ase o~g., Uroh 'to t at> Bin hnistre y 3 I 1I9'% (1999))G In o in emobodtmetcs, or n an: in enomd may be directed specincaety 1 t ortnm tisu (e .. syo) rathr uma lhe WnaleO noy 'The spcntAc treaorue ma beuse to t 4 -e tIb3ttY and inslbi omact disoi'der in cean em >Ybod0UImentb ih methods arc' useful. for prevenungP 4i acermiuVaue in ell wit -lip.oge n caacy '~g iver p -cra a mursclec cezs Meumod tor reducin or prevnting tfa acumulation in a ce-.! may abo,,ops ran mng she protein leel of a AMirn SCh as SlTnin a uan cel, oire a a yeast cll, SIl! m t eGans or a romtela of any or thes ains in otha r oranss naercasing prOtemn aevea roan be Ostueved by' :ntwxhcimg into a eel one or rnare noptes of. anuee acid. that encodeo N n F k eAnk, th- Ievl nf SRT can be increased in a manuidian ce! by Wttosing itn the masRmaiaN: el a nucleic acid c-ding SORL, es.., hamvin the mnn scad agut~n ot th j SA Q ID NC: 2, The nueic i ac. may be r l aih ameo. -a itnrmur a roguates tshe epesof the SHRUN ne&eivacd Abeivdy, Ito niric Ad nay be intoduced maw th aI a aiao te in enm:m that >s \nvtream. ofbpmtsWhd o nraigteiv4 of a protein using0 these methods are wrl loown in the oat. Id-mplay mhods are decried in the lxarmple .A4 A cue':ie sad th s onrduced into a ceui to increase thre p-rot-ein :vel of a rituin Uay enc a prn hat s least but 80%, 85%4 9t%, 95% %, or 99% intical to he ase e of a osirti, eag., SEQ .D NO: 'Fo example, the nudeic acid encoding -he proem may be at least about 80%(8%,%, , 9.mt {K%, or 99% identical to SEQ UD NO0: . l'b nucleic ac rany no be a nueleic aud tha bridizea preteraby understmrnent ybriditriOot cadtloiis, to a nc, acdd eno a w y sin o, S EQ D No: Sutinnt hybi n ondIsns may meldn o h lidvhrl un and a wsh in (t2 x SSC at 6 'M When ing a nucle1c acid that u d AN onh is d'0n\ u a dy ini potin, roch as a proin tMat is a sialt of a w y sttuin, th p tn pferabIy biological active, ea, capable of deseetyiation, It is only neesary to expres in ar ce a portion of the sirtin that is biologically active For eamph, a prntein hva todur8 Sup~m w'ildtp SIT pm ml co1n the cae scoe throITecr strucbo aoMiimni af to sam a in n2-9 of ti va -y human u ar oncoded by nuaolotida 237 to 932 of th wik-typc humau SIRTM tnoaeuv whb cotompatsses thew NAD biiadin. as wel a dh e bijg Anmsim Th curo domain nf SIRI Timayv ato wter to about waio acids 261 to 447 ofth wt hman SIR'T~ it tagence, which are encoded by .uootodes 834 to 1394 of the wil-type hum~an SIRTM Sequece; h abou snino acid 242 to 493 of the wi&typ. \mnan ST)qn whbt encoded by nulctids 7 to 1532 of the wildpe hm SURfl seque to Sa nowO acids 204 to @) of the widtype *htmm SXRTi. csn, whc r noded by nucleotie 8. 3 to 153 of the wikd-type human SIR(Ti squence Whtheora potein et0ains a. biooJgtia n1cuor e. deucetytbou capabitues, canO beterie accorng to meothodt: knton "t 9e at DelectNde Wna dp 0ad euene of hum)nid n ~rtplycmre donnm r oto het Shiauctode equnc amueacid satquence nsrved dtruji Sirr i NM 0U2238 NP 4 o 4&-362548 STRT il NM 012237 NP 036369 7331 12 NNM 03093 NP 9.0;9{0-9 SiT D ia M1 1229t NP, U3t371 138-373 ib NM 00107$24 NP?00NOI7324 1231 SU 4 NM 01240 NP 0 72 43 SlT I NM 912241 NP 036'; 3 P301 IZ NM Q11244 NP I127 5ZRUT6 NM 016539 N? 017623 4-2$7 SIRT^' NV 11653 NP0 P0-C001 M4hods for incAing~ situin protein levahi olo include mtethods for suimulating the trnsciption of genes encoding stdtns methods fotabiliz~ ingtearsea uraaNAs, methods, and othe methvods known nthe to in other nmbodimet s, metos of ativa L0tin ruS incud casin tho ilux through the. NA~h+ salvage" p ath a or Oducin nttfIuunnamio loes~ such a desmtihed in n 11 WOA 20v1/07 The tiviy r n of a n th NAD av pathwayat, SU a PNiC, NPTI or huma homologues hrof) or c ti phoshatbovtenferse NAMRT) ay e icresed Th hum gne for :NAMPRIT we ntom (se, ~gsans e 2 1994) Mmll. Bo 113,Rnwse j (200J2) tut t Ina 32:3223 attd F'ubsh et : ee 307:42&Y3 005) . 8739 an 634A W>)V. The ?equenc Q' .iSa6orm~ a e vlal un~der trenank A~ct~est~pnaWnbers N1 90746, NP 0037 and QW2O0 gnd the yquen or in on is ar , niMod ur uaky fher ae ado'tral NicoidkS mobtsde an erparTed by "hwg NMN (M n S'tntal wiea phopataa' :a dgecfod P9 inBogolse al 4.(004) Ctall 1 7*492 Nicennsad riboude epp in ti o>idze or edced fonns the later a which app9ears to $a QMj\t $ibl (FTrkedIpa a 9l 2') E~tx~i I1 haript 44;4 C..Maati1aid oeidde Fzfyuuw at atN , 91) a:depiclsdow ti.n ad 9~ 1 Iiomnd rapa~ ~c bdcand .fcwmae od adaws1 eptyit armuyk tnemP~ Where Nictnamide riboside can be contauati wioth the cell at. a concen&mo ofabu 1M0to 14 M caib ny be oztoudena aotaaed vith an agerdO that n 'st p'4e> o adivty levls of a nicktilnoand sido kias, (Nrk) ewsymp ibatp niosandesi ide to tbrm nicotitnamida mononwklotidaCNM4 lek exts in on fem in yast nd in two tr ia hunns, Ni (Ga ank Aceson No.M 01 i 1; 1PT. ON351) and Nr2 (G4Bank N NMI7eashNV73?4 ...... ....... s in hhtn? ot oin sa dn t o fo...... 'Thu Exeapa show that sittuin iniioyaentasuch as cintdodd inicmase l acanla o tidaga See examplet 2). Shian nhibtory op ineklde S omonnr1as that ihit ihe atity of a class it kistonn dauiase, sih as a aIstu in, and oushde for eaxanpia niotortIa (NNNA .14ri-"J023 (a dp in ytsWy NF279 (a purinergi eeptor Watais TIOk -Gimy2~ .~uutyhm 2ctag taesss (acpgtotel<tT . (hyd>. o ses 5 (4 p t dhi(hmy c'n saits 1a 4% 5; ( aoatech a ganate (Nydroxy sifs "A s and gaemc ete o ) y d itlnkwid (%53 ~ KN4 pen lthydaylavyiuia chi rt\ ddphiQdin dthIdda (33543? 5~i heaedmfavtna athrida); .myricctin. (annabisetrin~~ >X34% haaldnynavonel. al of' whtich art: thrther daedrhad in fl:witz at at (70tt) :N'anre 425' 991 COthecithittora soeh as airtioor tant splttosoichn> na deserdhed in Grozttar 4e ats B00 4R (ttn 2721.52772 senalog andvutvdres eithese .<..mpon can a lo Yet other sitnin iubii cy conaipounda' may have auf one of the filkwioz: fdono ls L L T (209R. 2wherIaN g indepnden k jbnealo atccu MQsece cn: a whcai Aneet 7tl 7b 3.h alaa d ce. b ------ k 4 n nak ' e aramene a rxs a n tar hun udus dy b a& frni E nt tIN ttpd TcblU (aIpounds for which the ntic to contei rate is <1). .Another enmpmod . Mercury, (%byoyS A sfrkdc inhibitrycmunay alsto haveS~ a: formta sekgted( from the group ut brmuzks 4S-5L( 53, tmd tP90: Witr cae W han N(t. M 0%, My roost, Aaen amlaa 4 nokt oawa Ns ttxcsents an>tyK 4kan Q1 tdkyay and ad d rgndwny ndoean It g rng msde H yhransyg pQ, A.y Q CYRovyiv a r iduuran derdw rupywus h O Vol cL o wa 4 qWAMON U Nnytsan irade igm ld nhei ' u J4W ldigen y o'a e t>rrne5 T. apriesentls U Nik tr8 0ndkvi, Cot Q~ ~ ~ .~ p It avvlkyi ayr y 1nOcimd oligoaadaI gycobtrmosyvt gvcppaosyL ghiurnoyr ghcumonide; atnd R*z represents fl" halopgenv, NO - SyS NR, Nodalkyi, argi or croy arprets andetger t 1 to 7 inesvz and b rehiet neae fri:- I 4 incdudvce (RR IN:T varda independety for end ccaoc I pse Alnt l . \I ' Rr pr'sats Hay dk y heteroadkyt tSk HmonsacchmadS e~goaccadd glConWansyt glyconppanomytggnc oeyi.or facutronide;and Rsepresents IH hIlOgadX) NO~ SR, SiQ, T O R calytaryianlkyi, or omboxy; arepremt an integer ~ in(10 in) hiv adn h ;poent fniningr rnm Ri O 4inciiagivc; 533 indat den t sp e e Z wo hn nadR dwonsa dedison 'eelAn ;an Q~ Im W!it H 2en mene and Q t srder eevm tadntc n A cold R!a i g rn mg ~eereishindeyndeedyin eackb rs At A 4 R , R" R, P 1V"nd R, ,a" - am aew y,.ihne i aryK raia~yhearocycly h 4vmeydyhvlykhessmary hlanyroaky. an In apMWns alkhadanoaccie USoaanegyaten gyopranr sy ~ x gicuOnsL~ gtnider tP5C~~~t 1C~1~~4 la &Mhe ambodhpaW &a methads ampris a compound Of nOamnitgss the la~ a ?f3x~ mTdC~~ tfllw(ja: l ( p 4~f~ia U ~annd Ia4dednidens when R is oill" in a AK moditnet, mhe tod &opngaee a comrpouadw of .imnIa S an~d 1e In a furthJr enbodmen. he methods cniprise a tcmpotuat offnuk is and th. amtnait dehfiitios wheein is is ORi i Si a id.he enSodimete ne methods~. . n~z connompud of thda end ±hue andanst definidenN whemht W.s C )Nti in a fer'er mbodhunstan\S hdscopYecmpun offN. a8 n attendant defintions wherdin Re is OiL hl a fSrther embodiment the methods captta compound of Zonnuk c nd the e "'dant defmihions wherein Rk is NM4k in a Ather noimen toe ne ethods aompnse a aomp~ond atnuda t and aitedant dfinntionswheteinRe is me~t~yl In -afteriletbodineni the methods cnipdise a compotnid of fornnia fi8 and the attenant dettitias wherein R is OK. Ina ther enibodiomn tte ithods eomrse a conpound of femuda is$n the i tgthebahrn te indscmre a komapound of fos% and the attendat definitions wherein R is Oi and14 is OKl hian hugemtinan he metos. comprise a ccrpmrd of Arraht &8 and \e attendant &fhnitions whereiR O.iLi Ra s CH, adia CIK In a fute esieonh eton prise a comspinrtd of itrmula 88ade atndant detfintos wherein R n Oilt is Cit R 2 is OH, and W is C((0)NH6 R a hnl aUtseidims tba method cap Wan m pnniz t'ural audI the attendanti dtoiins in CH4%Qn QM, C( NCAL is toOKR;i RW WnWt dcinitks wheti R s OR R ( R( U C, R A.S N N ".0 anga gD hia trheranedime the au hods eoyis -mpan veon a-an -" the'~~ Inbnd m nadamedenns mit is OW L R H OW R ht (H iO , R4 R, 0W Ri R. ud 5 a H h dr a Ho yan hdwr en do known icwoxyl oaabdnt U:n a c-ywdO nSTAIU MY oemso4 t*hnd h ad heten efinitinsayeryin t ies yi . i ddar ft 1 i L)U ft e-4~Vti 5O.i.i a d vethyn d s K au da w14wennatnenen zltreah m'ne ademi" " -n N -.
14 a tnmtheaemboann tbedndhods ampisa a compcimd of omuua 89 anid t marda.an detinitnkw wh4erin R is W a~nter emaaetoh nthoda compughsa omipoun~d taffhanuk ar9d "he wammakn definidn hra Ra i8 H. In afurther anodrmnt the methoda compisa anxcund oftinnula a9 and ',e attenant ekindenswhere-in it isek an3 R4 s Inadant, than etd in a futemoiat h ekda conwydse a comtxnd of' toomua 9 and a nd atbatriniinn t ed tbo a9 >saa H~ a oniffrtl $and PiihB *aktw .oiiion ttmn iu CL K , h-. 73f"~W~ r ianothor .abndimean mtods forin btin~ zin rotacatprsiaPng an inhibitig empon of fon s 91t "yal '.1N ~N R -ilkyl -:SOmoxyl whertnn independently Pv a e' e R. LR R> Lan Rv ae Hd ear a substiturted or it<bs ad al kykarjl. arslkyi. hamroclvt:ittt\'rydyelkyi heatrx orhemalk kt R. and RkaH, hydN y<'ran , sogasdet (g O~gther\Ot~ caddo katone.a cadmxydi wtn. oura csrtsimtd or s nsd.4tied atkyv' r aarsawi. he.meyystameyyalkyi het roart~rheteranoadkyl nzrersnas idkyl. 40)1 raaecbrida, Ugiachaadedlyof'manorvy giycopyrnoa'narrmunosy, or gucumid L is A NR, or S, tois an itger rkon (io 4 inclusive; and n and a atn idtoager im (ito 6 indusive.
lux a ~adhr emeeetMte ehd oiga \emUj.Kand atf foruna 9Oun th atant defibitions wherein 1isi U ha fathez d~iabtediarent, theinthodlds Oanpa t a td-gmp d Oofie 90 nandhe attewtxr d*)tijtons whereinA h In o. furtheretoe t the odt catapnae a cawpound o ifk 9()- and the ntkdart def ins whterx.in:a me~thy4 IIIacur m'dn" h oda co dse a COx ixnpaund of trioh 90 and Mhe attendantieidoran whecin m ax lin a lhmbeent bwdenent, the niethods cor rises a gaad oriana 90 stad the &mnaadfinidens 'ehatemR 4 s OP. i a tohe embdmnthemnetod ompri a compound of fonmna 90 and te tfrnadnt dc-nn: sw i a t i OH. In a Muth~er drboinent. the methods compiSOa Oesiipalftd axf tb aoda 90 anoh lsk'O_ A ORi=aw min tIQ is (IT tda d e i e W a th heanbhdndi the inethoda coi ad 90 ndh attend deondtans wh me it is H 'I a farhie'etbaitA, thenothdal pipse a onepeimad of buwa 90 amd tho rneda defidmns whernin n t i n Fi. iii a fiethet embiatdnen tha methods ompdise a igmped of fanda 90 dthe hi a furthea ihoafment he ase:heda icomis a cor n' of fant 0and the anendanikf whahrein iTZ1ndRi in a tAnthe n imenot. the mn Os no pds a tensred offtO nda9and te atidant de kiona whrein i R id ><ametaet n a fdrmnembuexhd-hnent. the m~etods com pric -a compound of framtxb 90 anid the aendat doei&r#ionmr esin Ri s .4 a ie Hif.1m s (it pdsi In a further enmftzimentthemetods compse a coinpmnd ofonnw 90 and ihr attendant denifionaw hedR iisl R is i Rs nth n1 io 0tnd iL O i " in a fAher eabodnsui Ummethod Snaa&se a compound of fonMdas0 and t atenant derfiitns wharain Rt is H t is n fi isamethytue RnisQ is OH and RitsisOt i frthsr ambodimet tihm nvthOs )f~t copda omipmUd of famtnda 90 and ha 'attnaandetioni shetnnit R it R la H ininWih m is 4 Rs PE R (' Ok 'Ind R> is it nas fistbetharrr aiment. dmeods compmiss a vonmpound of formula 90 and thn *anndant ainitient wheeini Ris H 1 H is i s rdyt km is[ 0, R4 h 0 f is OH. is It and R 7 is it intmdr andetint, bh m4'd compris a 'smnd of: JonwPl 90 ad th attendant definuiions whrein it HR is I Ki it R ism.thyt m is 0R R, is OH, 1,t i OH, is H. K is H, sad L dR in a funlr tesbdmesh A. etod copr a comnpound of fosl 90 anIh attondatdai htoa whbonu R is i it is nsmih m is 0Ais Ott I is O1 is Im is I, s Nl, ad anis in a fluthemr cmbodiment ths mnedhods comipris. a compound off trmada 9O and the atteadant defitions wherein R is It <is Vil2e5is mesthyi. iis C> it is OH. tk se OHT .R& is t i1.
4 a ia L and o is l lnhbbitory nononds nay also be ostdled fons of the ccpmounde of Tabte 21 An nxidWA Iam;o Qodeim aWb an acvar A la inohadd al nhansendedy aoeptabi additinsalts and aompkxs of ih sirta ithin(myo pounds dearbod hanin In eass herein the ptaptsh nisyhave onea or amore thiral senats, niess specified. the conpounds conplated herein nmay bs a singe4 flezeosomer or 'eNaet~ fl57tates5 ofsteredkomrs in cases in 'which lih sn'tuia insiibitary enompounds Iae nsumd ca5 ahn dou:ibie boads. both the ei C"' and a Ofi Imers ass "consmpated herein in cases whsemin the conpunds may' en in wtaeeC form sah as ke tai Uonites, ancb as OR ad each tauomdrm as ocnmplatd ais being insncied within the methods presented herein, whether eidaing in equilibium or klockedin onme fann dy vapppreistlianl with R. The manm of anyui as any one ovcurrence is ndepeant of !a ang, or any other bstta maing, at any other occurrncx, Also i Q&ladutd irie Io wihodN f k a h ie POrgl4 of the Sabin Lihfltty compounds derbed huin Prodags~ are c molrd to he any (uyasy4hi~gOde carriers that rlese heacIv pylons dA isr vivo. Met&i~e such iv d d ragd w mJ n dv ParaS d"SAT*dtbd reah 'Snoed Whether in vio or in vivo aiin inhibitory campomad may lo td w cel orin rd ther alone or in osmiVa wth other therapeutic azt i w bmlNment cwittan One so-win . bctak With a or admoinerlOT For Oxamle, at least 2, 3, 5, or 10 difMrer sin aiji i Orompmd mciaybe comactedh with a. celt or administerei in mother hmodinxent a sittuin nirtihiory compound may be adminiserrd as Pon of a combinasio therapy with ater therae-i Agen. Such Cmation thempies any be atnistered simdltanously (evg more than one thewrttud agem administemd at dhe samew te) or oseue\Uv~ywaa e~. difee n or tha uic agentU adminered at diern nesun a eatment To primic weight gain, nt or more irin inhibitory compounds of ininsos 19 48-51, $3 and may a usid m cmbiaton wi9n phe hollowm "wash n cirom>n aenta. s esctnxek (su ich so gpr>Vl), alphs biatkes (s.as~ ekidine prazoain abd zemosinA) :iul, sulfoniurean(suc as glipizide andgbid th.a)lidnedlues (such mr iegliazone anid roosootane), mnegitiis aegid, ithimN carbmale, VA acid, a : tie nt ending, o vonmpk;. teycttos (such as samitriptyln hnd upnuine : mnine-oxidase' inhibitors. seletIV sroonwin auptan ihises 1SSRi)d baprpion. p roet and muuapine, chorrohine. thioihimeo ntis (suc a prenotisone), soa contrcep've (bith c~mto pi' Ottote comntracepives containing estrn and/or proesleronte (Depo& Promn h Nori ant, aUtst 4temnew 0 Mrgu c 0n00nn01' embdim2em. Oneor m tnore llinain 1 in .'ry csompmnamytO IcS ei dirsced pecNcat5 to U cetatin titoue Ine, .0"ier' rWO b r thue Te whoum body. issuC SPH =mho in a 01 hds i r saaat g C a watino to rtgou laa CampUs do vagd e protein lvdl of a srtuinn tocnii tteadn prtn tend nte acheved accordingt tds know rdithe ar n edmnpk tian RA. aanntiseman d0 gmearetea.
sirtin canr b xpresed ik L A a at in not capable of des. et yhwtingay b e eeapeetn 4Yo ir ascb e, inL et. n 200A COB 10747 can b Wsed. Altemrwvly.ag %Qt: that aKIbKK% sCuption enn bet racd. Inatea Cbodaimes, a pound deebd hereine a aun activaor or rohkor.daes not have signpinent or detectehand em xidat aadvites, aderemnitned. b any of Ohe sie ~anrd saS t rA w , S e a t For e Im . a xmptmnd does not aignikardly aceivcnge frIt <dieesuch en Or radicals, A conpoand rtray have ha than atZitt2. 3> 5, 10.0 ore0 lA anut oidn *avity rnze to anther ea0n Rod rstrot A comptrd may rao have a binding afiuS~ty Z~ foa zn of um 'M N 10rMh roa A e mposed ruay rdne the Km of' again 11r ts abstrate or \A~ 4 ra tfltor of at dent. chnt ,3. 4 0t 30 ' 50> or 1XI A rranspotm j y iaTsa bhe VuxW of a sWetia by a ctor of at est about 3 , 5 10,0 303 450 o 00 E<ephry coip'mqdt hatd may Aae the Vax of a &tuin inchide for exat t aogs of soniDodvnaumid s ucas, rample, oounds of remadas 1Ram(r analog; of via aeyj g boiul affte lecmonso onbs I comtpoind tmay have a [0d0 le actdvating the aacetyhas activiy of a sirtin of kasa can at I UNt leWs thanaout W 0 i uti ie. (n caut 100 nM, lens thnu 9act 1 ai keas han aoe 10 gM aess thtan abot 100 Mit oe from ahont LI0 ri., hor about I >1(0 N: frno aboi t 0.1 jiM, from o u I .- 4 10aM or fian abo t 10 %gM A compod may atl atn i'h e deseaylse hdy of a snun hy a ahtr of at at about 5 10, 20 I0 50. or100, as rixeso red io an aceHd~a- assay r in a~4 cellbasd ;55ay~ andesadbed in the EnAp A cmound may ause at (at a 10% 50% A% % fold $ bld. 1t fold, 50I foi o r fkiJW gmeaur indluden trhe deacetylaen activity of[Ti relative to the mamesec cntradttrof rerwveratrol or tiseatntpmund desceribed hereirt A comnpounad may alo havew B C50 for aoivadng SIRTS Mha in at least abon 10 old20 fld. 30 (1d In fd great tianp tatfor dvtinrgUI'i In an exemphary emboimen threhdsand canmpositione deseibea herein may Incinde a eontdniin Orhetapy ~ cop.nia .es ,n.tnnudan copndta adoche mofa 'inrin fior its sunisit'at orNA~e by a factor at lser abut 2.. 34 I 4 is 20. 30, 0 or 100, nd (ji) auaat oe sirmin--tvaigz compound that incas tho Vma of a WArn by a Waxtr of at .ast naat 2, 3, 4, 1 t\ 2J, 30, 50 r 00 h one Cmbrdeen c.. n o*hayy co.priae (1) at It oate t A compound nay traverse the cytoplasmxit mkhrnme of a on For exple a ompoai tnasy have a dcetmabilirY of ad ba t 20%x,% 2% *0%v90% or Compounds desCAed herein may also have one or more of the fo&iwk the campouad iay be essentiaQly nontoxic to a menr 0ceadrot <:ri coggempod may be an organic mnocal or a yonalmi lakl of 2000 ana r r t 0 amu or .sma conipomid ray have a hadf'if& undrooad annospheri condihens or at last ab's dy daysN 12 days6mU at I yea; toh comipand may have a ]hialife m a A Mie fsea bn , dnd as 120 dag (s moalLgher 1yar, a cog a my be r stable inzmo tharascrsa y at last a Nonar ofaam % 2 . 6od ', 10 3O fold 50 kI d aompound mGOy promOte dea gNddie DNA repair factorKmf70 a copounmd may pronmote deacely nceo tA/imO a compre mdray nmYSoer rames and naofn the 1en.tivit of l to 'Nladied apoptosms he eftfet of a compound cn the activity of a sittin such as SIRTI. ay be determined as dscdt ehinowitz et r supre or as fthows. For instance. sittuin prtinimy heaed co e compound in vitro ' in a salutimor in a cell. Inone emtodimeat a sirtmta protei is countered with a conspun in a eoittton aid an activity oi the sirtmi is abflty to decelatea potn, sn as a hatonic orp3 or portons' teen ot a tnm;smed.( Geerily a siki e actsvated or irhit daa apedrier at &act mc of ts biolodeal eaciN cag. cmerylation aomvtyu i highei awa etpeOCIVl nthe presence Of thecopoundaanik absofnec ACdati:ton or 'i' mayb bylva. e of at lt aboutO0',0% 50%, I00%( a lixto ' two% 10 t or I M Wlheasirtai mactivand on ted che derermaio de e,. by altding th 'ma a " celo' Chutract 4' .sftn d a v, u ch asa histone or p3 protein or onions thecot and deenaring thevel of aceQatizof a the deacettation target A higeser leelo etylation of the taget :Tietai wiih te iinnin that is Wi te nAtivt$ r e tlevelt~%t~i of acviston of A Ofta indi wes th ait th4 md thd beingteste 'is 'Ctl.sed Convasel~.*y ~e e; Sf..gYeno the- ge ,aAd with the ittin that is nested Wti to the Meel oaetyimni of a or Wsin indicates the he siriA . that is being tested is nhibited The control tujn may e a mnhibitngr compound, vly~~oe~t 'APt. " , -, Decbed herein a raithods for ttin or g reventiig <A,ty x i ght gadny in a ibe such as to .adce the dght ofte suhjtoren 0VaPe w tain A mtreaod mayt compnso addlrtng to a subpoA. 110h as 0 jelaA newd lamc a phagenttic~Ahn titve Aaoutnof as agent ethat ireases t actvdvy or p rtin kwCAe} Of a Sri, tech TT tr Sr A bj in nead 0f sue a ra zxtment may he t b who is OCsA Or ikdy to bcxmmabtseo Who has, or is iskAy e gain excess weigh as ne~cted. e~frn tamniy history. Exemphryagent, a those descdbed hanit A mii agents m s te 4aanistored A InethOd nay fV m r mmnitong fgth he se t r the ootvo otof imtilss fexm in adipose tiss Aiso desribd herein are methods ' treating or preventing a met ds e su as aulnw resistance or other r cursor eymtom ohype t daeety o I d'aetes or congiictions herotMacds ray increase instdina semshvity or deoreaso insulin levds in ject A method ay ompriss administering to a ttiect. sdh as asabject in need themida ptaxracntically octive amount of an agent tidincreases the ctiviy protein ee fA stmin selas SIMII or Sir2 A rudat in need of' such a treainoeptmy be a subject who ma inslin reassance or othe pcosangn af type I didhetes wh baseel diaheteth Or whor is likeby tO develop tkat 410hes tndttions. Farea e Ashoc t Naye' m'yN a sject hsav W Oinshtit {an0 te g hasvqing oi entthti&g k of hypaibKastepremn epaied &cse tolerance, high blo ghics surgnr evel, Kthe manifistatons of syndromeg hypedenosiendicttsro sis.. and. *pdstoh*ep nootsetose den bedherin c In A tebnto of agnts~ may ao be am iided. )eto6 iay Pwther cm monitringrdhe ubjethe tate f an gth sit3Oaddu tndlar the leVC1 o avsktiom o sitior:a te mpie&Ih dpo >ties f t Otaew mh ds tachue adiisring to a stject of" combination f a>nagnth increase the actwviy or protein tevel of a sirtujn and an. agent at inomas advndti or proteral.t of nu .AMK, gp tezan ain agent fne ates a irili Akbatsof' AMPK. iutkde MAIA N oondrne Aktnadtefy4he rotn level of' AMPK may be increat by intducing inic the c&d a nudc~hi acid encodingMP tThe nuletdae seuec of thantlytic domai (l oftuman .AMPIK has the anchotide seqe sr et tort in G2enrak AssenN NM> 0@ 'dencdes protein )usag jthe $anan X aid3 eset fort Oin ank Acnon No N e Te numleotde seuecf te nag tde afir ($1F} of hm an AMP has the ndootido ternc set .rdh ina rna A No.tM0%22and encodes a ptetn Iaving the ain. acid seuene st fttE' in Genank Ac eanumrNo. NP 006244 Tit n Ideodaie ce oae nostacn amah (yi) of Phuman AMIPK Ehas tie onudeotideenece net foa i Gen~~ank Ame siO .o N nn d and medeg pmn.ao aving. t amirp and. sequeance sets ft to; GendanklAcession No. NP 9%726. T iceesse the potenriceve dhalmnz AMN4PK in a cel jt iaay te necessary idtoa r ue kic aininciniig ;'adh of th sutnhaee t p r otn. Nad>e aequnes enodn theadifeient shtrsn mab anedn the S ne r senate Other dsae0s thw may be MWn by adomitrteg an ager Uta irereases tre acuesty rroiendvd of a inn salr AMPK in':de ceta teO4 disc:esn dn 4omaenrdonkphriiglmnk eow! sneprroic syndrome, hypvrtensie nephaerosin These comrpouinde mray also be undfni oar imprvng: cogditine unetikone in demrenti, oreadnga diahoe 0 copliais earrastipolytgt'i ovarian synoe (PCOS) aund preCenonI aud treatment ofan tes e.g osteopo.ngsm, Adtion4al diees anid tdiown ta wil be)tfit kt weighira and ca Obt elesatemrt rsysipdens. type 2 diabtes, insulin raiStende. sghaorsetoba garanaebokeystris and chodhasi. goMui osienrdiasa Ohtraative dleep apae add tespn),ry pohams sore types of cancer (anwh asa ndonri beas potite and cdlon ornmplear ons 4f pregnancy; poor ibeato reproidvv heahb (such as mnvnsrral naatinneduri arid nephitithAsistpoaganologtiesi disordea (inh as deression, eting. h*UAWWrdor&6 at4cid OQAAII d At \Vatktt I admkre di>erte ody itaOdW rdf eakaa) Stankot b aa Tddti Obsethrorvtnd trrpv &ooxAd Editn New Tht: Raca ?nassu 1993 TNo2Pv tinl Wh .. A.DS ican d.velp ipedysroph or IstdlA 51 5100ce 1n Znrspose t combimadn therapi foMr ADSfAt. b Acrdyofoso W3ndhIon Qnd betreoatd Ot rewmtod by tho hods describe lirdn frr rttdudug or prevenig wgthap& Also rode here in aret med f o rs ztimulating weight p"an, A zntdd"d comptiss *'dhmsteflng to a subject such as insobject in nceed thorot amiceel cfrcnwe aSat of( an1 ageT ~th t% ereaSe the andvity o ro~'4t4 t4n level o flan ouch as 01R 1ri2. A subjeoct in Yneed1 SOf st a eatment may be at subject who hascueez or likely tO develop Acheola.Eemplaoy agents fose described hremitn Aahnakatonof agentayatto Iae sMntiaOtrd. A :edictod y fato he etcpr. aaat og. t su eet lhe stats fflbs isea a55t oftudenf sirtoaostr oznsi en adipase tisas Mrethoda tbsr s hig Fa niakon ils am/be dsed 1041 o, iuoab nil Ic0s. tO we ak kig whidttty tbe 98ed~. Ito dooifying olbo dotPc Ilot prOVend. a the hagain A mtod for simahin xvdgt ga~nke rt fet rmukaion aa ed or sijoe jy fiwbor cmn o drocasrng the actv . orpro level of an AM KT t m on achieve~a byin kn the xprto transeption ta lsation or poSttnslationP mdacation 01 a1 1east one5 0.0of tho sa of.AMPK 'uch as the, c27alivtic unods it 10011niques0 known in the art, su as Rt4AI; tadsentoseand rborymes can he used. In aditinon domnant negadve mutants may .es 0ressd in 11he csi Dominat negauve runa auth as hn g a ovadated AM9K alpha shabara desoao.ed~g; uin tokwthl et eM2C)04) Naitra 42iM5$t>hgng id 2tui) 3hINo Chant 2 22 sad Woods of -i (2000) Aol.Cell1ioL 2704. Conaponds that ithibii AMPiK o nresska or adtity mv also be usad. An exeraplry cnotwad is deseaibed in Zhou at al. (2.001) .(Jnx kn s Also pro vd hreinot are methods fIt oodatng adipogeness or at l diersniatoi. vdl.a,,hrn a ro or .n vds. In par socklarhg iothigIvsn d ioh and~or sara like gro h tor GF i wilbh prevented m Ioro ruitingpaodipovtes to diferentiate into adipoctess Such tmetods may be used to nodlnatne S A ntheod fordnoditrg adipoensisA may a pomris clatwncng a cell wth a gn tha inc eass th $13 *aRvt o pmo4 e ox a sitn suac as sidin5 ac1Utg om Ound.e Ciampond desanbed herein. A edhod in a~Ting~ adp4nss u.ops cotacting a -*d0 with an agent -bat decrea the aodvlty or protein kvoi of a aui .su'h as a ontin Bsdat ieat on th fd~ didresatna; as been shown heroin to acztvate AMPK, rcvertrol and sthzr strisis acvating comSpound&1 n b44 e usedJ for treating or nweenting 4A . ;onditiona hat amnat frm AMKr meiddaion. eg. wch amea sso ated with andlar n:hed bg AM-PX indiin to those'doeried aove ii phbavgoonditions aid ne ciUnie syntiplmNassociated wkh hypoxia or ischenmin(mocardid infn'ctioo. stroke), andi dsCrdktofnupAti (sew US Patent 6 124,125). SiAihd anynomonnd that attsates AMPK may b i xed for the saue purposes as ~ ~ ~ ~ ~ ~ ' Whd towtin copon, ma)b used gvt exen impan tomake Or% nrliI or a.ISS tevatU~ )tttmmoOW r' bt p~ 'A' Uwmcd. wa in atm e in' ISM. t a I 7 moo aitnt stress and to protect et: agaMist apopt Odhormnethods p Inoed ttieein are methods for retidc appetite, oirasg orAety. thereby casing wetght less or av ,aeo of weih gho may include admudatrtnuug 0o a subjMe e a bjeet lt need throot an an-ount of a tda activator Kor5 4n K aget that SYiX4OmS theO proteint leve of a stnin ijathe subject. A subjectain ned of sch 5: trAtenmy be a jstic ho is teeaht, bes e ra as subjg l to ecrime ofegigtobes Thcandoemhod may compiac adiinn dauy. oveyt thterday, or mnce a weds a d~oe SA.gQin the fim of a pli~ toa tubjat. The dose may heas. "appede reducing danYSuch a din may be, Q. one pil flnw 'eQ"Nd iy Ass ys for determining the ikdibood that asubjeat h4aso ill dcvdoi. weightgain. o$Ssity, inhikn mest4n,4 diabetes in; preu s tOna d srreding thereomita ah provided.auch assayw mays compse detrining the lve activity or exsioo (5g ndttA, pimRNh A s gotein) o a saxtarbsc as S'l$f 1 or AMAPIin a nbjvet A TnW eel iy o5 tc94ion in 5 iatiOg9 ely to o ieicate that the ense-xmct has wr is Likely to dezdhip weght gain, obesity tesin resistiuce, diabetes, riecron symptoms thoreft or seondry ' Odios therint Miterniatioel a higher level off shm ctivtyv or expcresson .nya -*< sjetS likdy t i oxeate thst 'he iubject 1bag 5uia lika to develop weight toss Nad be protpated fin dovodoping hihiwight assoxvted diseases, ch at s inadin' mtane 'and diabetes Other assayaincIde de ra the actie-ny r klee of axpression of a situin and AM'P& Aim pvided harehn are metho fhndentifying comtpounds tbt mfodiate oditO andb t or preventnrane (or s"11ii0y or dihab.et u o may eonpds ideiig an aen!t that Wtodiates he actvtyorpmeinkvel of a i d tetig wwhtik the test agent redukded weight gm. and/o &vn be used far treaing or nreventing irm reanne or diabetea, The frst stop of the method may comptnj con'tacting i .na a teat a d nd 04 mi t heok edo t nes agent onth ouv of hesion g ST * sa: deribhd a U coa it in a m he UvaS awle of the nsbt ne maltio comprke contacting S xdi empshi a %nVuI inh C test agent and ig y ofo e ddrligthe ezt of the test agent onte r'a o uexosion lev&: f de atin Epreoaien lee; of a srdr may be d rmed by .ossrihg the ndKNA ptrsirrNA or protein leve. of the orturm.r thesondoAte of the utethod may somppise Qtst teog raa aernnai model for cbesie insuiistarice and/or diteea Such anitria meds are 41 X1, &Zua f?'~ u~N okx'kam " "J we1nn " the art ScTeening meeds nay f.ur e Am s Op s th aomn e ah totigo t ddv 4 kiestettoets Of theZ agents. Uther serng asatya cOmprise idetifyttg aens that msduito AMPK aetitiry or pinn 1v iereta need the congands ttat seivate AMPK but do not have the toxik hoe or adverse effects af known AMPK ~ ua o aevtos s.sieint 'ensen Pnalermateeai compositins toeme ia >ede waih Oe prse enia a be fonrudate n coveniosal sann uing one or tesom physhao ' aly aetabk frd 4 "tS Or~ .tpimr.. TIe. sont uannaig or ianhiidmg mounds ad the i physiOlogically acetable salts an solnates masy het; orumaled for adminisran oniefe~s eampnwk ecion huriatiot, or insufflation (either through the mc> ed' the noe)n or es batd garenteral or rectal adminitierraing one enbemnt the compound i dnintsdend WocaUv aut the sie <sh re the target cells 4g ft cell.ac pSoi te adpOse tissue C ompa: can be tmmiated rata varety of laudof administatioin Eindtng sytendae an~pe <. Meje a~nstao Tegng. and terasdtins enently ny bec trodhiRe:mmintont 'a Phanoaceuticafl Seenes, Meade Puhda]jg Co<,tiston;, PA For rysteni skdnstatiotoeeto is pr4kA. innnaemo senta ntrrvenous, itnapr.toneal, and subioaneous nor inieotion, the compounds can be I miukated int lquid sointions preAmrbly in phydiolgiudy ampatiie bets anton as im k h r ngr o cdapsled drada pm . .ney d sidfnr atnd (Misophu"d; lotu dd t AphaSf. y meaa'On For ora admi Ton ~ the ph nowu~ia composnos may too the Anna o r empie ngs r capsule pepare by onvnina mas prmaety AUTetbe ext WOM nts aucuas omiun an teyaky pr0yane W&a0 xi o np i or WIChydrop y and;hyleitiulose); itlse (g 4actose, microerystalline celluoseN or ca. iimn hydrogen- phosphate); iuKSiamte eg. maneiu NW IN'tdc I~>l 00jSilita duit ?at f.g pota-4 31*' "a t diaam starch giiC late); or wtngasems~ 'eg sodkim lar upate. h iable may be coated by methods well k a:i thc , I. lid pspnaratio(n, Unr '- adgwisatioil :jv1y wn, h0 i r ramp stoinos syrup orsse ao rtheyS ma bet pracnid asi a dry psroct tn): co 4ato with wez v or et'; suitable vbhi bitr use. Such iquid ppa2ssians may \e Ptepared by convetioar metams Wt pl ac eptale addiiives th ta suspendig ets (egsoit os't syrup~ -ce!ose~No enaiveS Nr bydaogealttd edibk fals) ketily n ta\ 'e2 lethi - r tcacian non-aqou YvUlAle$ (e4 atto oiL o~v est(kr y lOnAY or iona4Wt val " ); Kr vv -e-.. g. , mtt or ppm or rbc ad) la prepartios may aso aotain biffer saiTsc. vo-ng-;- olon-y an sweenn agerds~ as apmda rparahton for oral adOitrahn may he sunhj :orutted to give coni'rold release of' theao v csncill i Vp !!ad to' 5'mi5OWI formtj, Ta prevent oxd tna presetirve th tun stimula-or az tvy ofplyhm oi i-cop- ns th \ckopoun.. ma hes-re, a nimga amophre or scaid s a a n l paag h vubiidhedg OW 0inggo -(he torm -of'an aerosol spray prstatio f-rm p.resunir pacl or a ebuingz with dhe use of a suitbl p~ZOpe0!at, .g dichtadordi ummtae-, tddhlorfrmahanet &NtorctriuootM. catcion dod ors inr stmitable gas. En the caeo apesuid teo o! Aadsage unit m-5 a bekdtermined by providing a vaveN to divear amerd Uioasa, Oipsuls and ouaiis of a.,. .stlutda hr GS) in tO) :italtr ois r Vlt>o 00ay be tonmiateds cohina pawtr na of ta sepound ard a statabs posiet bassanch as madal wnaek =sakoy ki Theu compnds roy bpol frd for parsmterai s strn M:yAti on g b Wb~1 ttaJCwtO4 s my ooflow beuit s 0 %osfx a b rsoo nit dssage tornye aIn auol ais mxoiden doss ianlin w an 4ded preservalws Th somposit os may take such Suchss luoensns h on om onni o Tgns vehidee. and vm y contakn adaory agenta *suh as suen ine Mabilising ander dip.n agns - msltidy rth a ed sin ay be e.pwsfn o ~~~~~j''k "'yr 8'x A k A~~Utl. 44U' V'Wm a.r**K mnkstitudken with asauitabidvhkt. e st il pwfnie water 5 nfor"e s lTeamtponds may ala he famrniated in recta comepositons such a pposita .d or tntion. s-remra& cx.suainirqgo Pen esI nlapostsy baase auch as tCO Os t(:y 0 hter gly rodes ,'K addition o iha fammations dssedbed prniousl.the aonipunds may aso be formuhad aa dspMo repratiot. :Such long acting fomalatons mayv be adittre by Iho, plant for e pte tn' orz in-eddythy t ' wie ngsnhIcyinsrior b rophohlematias (tor enp s e nsion in aseptnk sil or ibn Vehange t or as sprkungly so Aufi deadies for x n ple as a spadn sonnk sAt. Mm4Atow lA '5 4 O R4iT w 44 wwk,>N&44h . Cpnam Ua. noeleas a d indiede a Phareaid ropo discna (ins ug sdamethe pr pa latisn may sotuepseom 500o4 PtAC0iC1 to 100% suc aso th 00 Ito i0% or ftha 0. i to 5% by weight of oue or nnukaionaniin a toptost suarie that is genrvdly suited to toptoal drug adm inistration and .o agayschuad nw ieeat hioidc.e a be selested an as to pnrvie: th~e sonorpsito n the desired formg as an sunanwandloonn cream, aiemanvision, gm, uel soluitixx or the tikse aad m4ay be comprtsed of a1 material of etesnatataiN ocunng a r syteti oin.i is preferabze that hese ied~ oarderno adversey atna the e'tve agr or odir campornntaofthetop:WsI thtmaiationr Eamples of sitabk) tOpcal "'Cartrs fo use eri included water.alsohrssaind other 1t(txic Orgarde) maoivttutiy vtuurto lu~ 0 minducsious.pitOkin je y5na04 fai, ada ~veab aiS parah. sxrss and the like zRorannations may be cicises . d o~ r iflnzint ktton ersenaanieroenidoNa~ and gew. dampoUNit y ecorported may oia)"tmet1st whicht geutaiy are se miaolkd repu atonst whioh are tyyalylbased on patreu ne' o her er Akut d i T seefic ointment base to be usedt as will be appreciated by thos :skih01 inthe ad is one that VA UxWid h piaencnWdlvr. nDr m will pr'ovidei. for trsid daaretristtes as wet em enoz or the Nke. As with other carriers or vehiclek an onnraent base solid be imdn stableonirrbatag and nonseI=tizing As exlined in Rerintin a eia the pr..in Setktt hitentses rS ab arstned inibi touee Oughus bum n e bae; emrisixt bastesand xaar-sdhie bates dlginomu owlneinu bases ialude, fOr itple vegetsbi aus d obuned fret rindl and serrwdld Iydv arb'ons obtined inoin petmaetn. Fetinsab oeit woth1)se0 als oon as abanor <int bass contain lEtt or no ter and incide, fr example bas are either watettia oi (W'O) emulsions or oil-amvetr (OV enaf ad <okr example Wert A Nachot glycnryl mmonsaeem h and sAdN4,n d Eemplary water'soubk ovntmerd bases ar prepared from pOfthy N (E~c f varyinemoletat seighnt gain, eference na 'a aud to Remngtosn a sra;r, tfdher Qotmpoads may bez. morxteied into loions. eis goer'tis'yae teptatons to be ly lk Wt or quobid. apple en to t 'ae thft5 a t toutt 6ri0den and "0' typiedy bqie rsmie prpaadens ir ieb solid pardices, in eding the a o 'tiainare paean in a rater or aohol base~. n Laie e nsuaily suspnens ox solids and mstay coenspi n a iipi oy eudsionof he Si in-'ter typeltonws are prevrrd numlatons ftoet inea tcbtdy ecmoe of thcoore of app gcyoinposdon U Is gencdiy nec(esary that the inacdbibe mater a ledetn be finely divided honons wiU typieaiy contain suspeningeagents to produce bettor dispersons as well as eonmpoanu efl for localidaig and holding the active agenT in contact with te skin e'g, mehycelhdoseg sodium earb rbvehyielloeer the ke An txermipirylotion otnuttoie use in ctonjuntof en the present methad nta inpy egy mie with a hydi ger m such as that whch naty be obtained nde tetradernar AqphORt fin PBeiersdorf Inc (orwat Cum Cfarmanda mintay benmaa IrO amn WI tte~oraR1 &t~ a gid I>, and*Cwina W0 ntans, be; SWd tis at an ah cmpid of pt boy m od vsy tILohol wait sc o steay alw ca t ae ptwe sualy, athouh no nec 1ril, exceeds the oii pasc m volum' edn erll Ktpr is n tll a Hnoninniioi a c atini otamiahoar striaui.rdo tvat ol ad nwt; suM by m orft i Aicm of surfaios uleuA &ncycopdia 0f Ph~americalt~os T ncnology (Nesw York: P.l D r 002 vdn 9), or the Phasn am a water' phase are ncessary, Sitble su-r s melude any u a h idbl. in the proradon of emulsiont cxgt .etaser dha arcojpcaly used h ithe prepra () ofl&as 'The co fc' tan ' Ioeu " isgnealyslcted nom (he gruiof poivwivoem) derivativeo. eltiyriaiinarss r an ato'ty ohos. Prfere mc ans~ are generlly annough ow t :oarily HeM Ao the monp consistingO of:' lcers mastoatato and polyroxyethyvene ste irate; potyethylene2 glycol to ehln gi pmtoete and capritic am4caprie 1nglyricde and s leo Oraro siryearis. Th' wat'ar phaso uachbut not anly wates be also hyicalUy. buYrs pclycshylne gyctol (a e1, PE 300 and PEG 400), sos yi, and the Iike, wim- 'th i! phasw gyena' ly compri1, IV e.ampK, Antty acid WrNA miodi v eetmA mb\ olkoy! matcr"g0% glyr de etc. Comiipounds nay be in>orated., mio~ <kes formulations which generaly are sormisobd asstmcsis.03titng of sitter em ienaio.nS made up of small inorganw sardcls ( topas" mm) orS510 @ " organic moleUuies distriutcd subtanu2 n! iniformly broughout a. carrier 14quid (single phatse gl:Y Single phtaszo getsa be maodo, for e'&ampik by combiogthe acotieaget, a carri !!quu and a sutabie geugagen saas 3.:*.5 oiuma 1t cabod hyisellul o: (t 3. 4%), < 4aoe fa .&5% or~' pW otyvm' acaho (at 141-2%) togeher sand miing muni a uhracrisic memsotid pmuet ih' ifS .
prdualQjsr utable geSlng agets ai4ciad meiyhdGydtOSplCy~cC aqueous carrer lquid, acohols mi oiHS can he usA as :e ano; lign1 ts wdl. Vwreu additive&: known to those tsUik lle i the at ma 1&e inCh)."d in *r4yNse44 tpia t2nlai n~,wNample o,.f adnv uuwha u o hie galIng agents, buIferng agents surfaats (auiuymincand apol gMtC and h i. hxInsion of olutizc, ersin/o skin penneation enme paide uPPlily I edOng L.whd em~tdhevlN em*oil ~ils ad~ preservty'. 4 An Od topical s)mmhMin compnes appniate'y 2 wt % to 0 wt %, prefrt 2 wt % o0 wt. %soNthzet nokI pnmeedio enhter:; 2 wt, % to 50 wt. %, preferabUy 2 wt % 1O 0 WI Ot$.1e% 2 W4, : to 20 W t oist; 3.id OA3I to 0.. W, %e Wid1 ~ - Mn ah C~ Se~nd CaiS10 laq wow"i making Ass eendiO h ED~slR A y\ms ermit. C er scr'e to piiitn plPO. :0 ta*0teu!N was oNU am m pass t t rnb sed Olsen ow! unbo ken km. Suitable "tIamner. are I me! Xnw in th m mlcld ' h aImpk: iowa aXanols eenh a molC' TN di 4 o d o akyi methy iId sne' as Olimdyhexide (DMS tQ dcyimeotnhosido (Cw MSPO) nd~ tetraec.ylmeobyi sul foxidei; pyrsoe s6uch as pyn'sldorte N'mety2-pyroidoI'e and N'ibydm:Cyethyx pynedone; urea; N N tehl m-tOuaide: (:> A. anedi0"ola miscllneo sokenis suc as, dimethy rocmmie (D)W NN maiethaew m d( Indl ietrahydro;ry alcohol; ad th substr-da asdd onpriet adev,!yu teaIaeAe:plan -one 411nAf$ MW by! solubH0 >oneI pbuttnh tw 010 U s auiMykne OY Uohnenohgy, er n ado o xNU coa WONDrea, TAWWWmal and car y0uae dnmbi i RetA\bl cony'nrAyw SON "AMRP) p-gehyln eatfox9saWe y 35gnonse o" jyany 4.' Poydhy''an "Assci aspAk35atad ndd 4 su $ as4.n1 4 $t aprynApiyx.14 wdesYt a'eane ataarcalashnaodti Ivs ahySyIcdthye p y0A o TAn gagn yoniidene yoed yeh0l ynidagA DMAA.Many solubilizers caa also act a asorpdion enb~ecers, A.e1 ecbtlhizr nay he in a anLonthe ft 1Mulada t aixuesr tamieamgya be ncrporated there:. and . eendntedrsniedbed with rerpe4 to ina\ nitiajn hAmucionan oliints 2: JPQ2) ryaty e r Prapinat; ed thRe ire Other activecaens y also be included in f nations. ene~ndr agents, ana:ris antiniar&bid agent, antitktngd agentse atbiiti 4 vitaminae hut nO~iited to~ ahramite breiphenon (prticabadybnnarsphnee)3 tnnpher derivtiest dinrs Ceo. octy! metoy4 n -t)dhezy mtaes (nv brv niexv dienzevy t Uianh p-amnatnzdic a'd' A2 and derivate hretn seney tes~g dyl smyl e M erta I topica .raml adon ore aagenmt reet IR knr avOo t in ine a nge w 5 II 9' 5 t, h npre5 ofi the an g of apporenimtely (L25 wi % to Siwt % of the .hrmiriann, mte ptrretib in the ragce of) apoxiatedy QS .5 wt %~I to t3 % (4h thNa int prfdy Obe un o arppmu~atedy Li wet % to 1 0 ret of the fimmetioe fugieai akin tiiatent coinpoution t he packaged in a suitab autiet to OM its vkcosliy desiede tsrbytle ci)ncrenot exart a lotion de n een peakapdt in a bottle or' a .ram. applieatori t a ' p 'het.den ontrla device or a con Rod w h a pump MalofX t O ng etosion k 'n stfl maxpxddeN are{ ecan i mpy batored in t flbedbor ns a ue est uc a b or a lidedr Thek cowpoition may also be inuhded in capanks sh bn US, Pa No $t07. Accondingly, also provided are closed cainners containing a coswetcay acceptable costin as herein defned in an aenatieembodiment a pharnaetical fonnutininje provided for ram o pcitn huir6atioin in which race the thma Icton may Caompce an cccidu con pooonkinnamicroemavt a"on a desd avnb 3. uom eont irt aneate pannacletioahy aceptabe carres victas a / a a ud r parenteral druig adamnrraadon, Altenaue an actantinga ro'mpoundt-eontnng Adirmtin fa tta actvaor or~ innibtoT Pmay be00 ae by~ meanur a factor in thea subject, sucah a~s measu fring the : gedyty o thO $aI$mIn, han a. il lusti umb xment a l ha fa nnaro a r> subys tollowef; dOnta ano td an ac.tonn aA.~ nitiing compound to WY , b ain a Mp nd te Wtv t lcunm or r uin 1xp Msaion M l dSetrAin d in dath biopsy invael i omERs, much ay plasma bbenrkr may b wed. a s may be adipue a.. dived secetsypresu, uc 's kpun waipouAt4igh and.~ re-i.-~~~~a Th c ma bean (e0f h >;ect, but in ,:e in whiah an acivaing zompnmds adned a the c4 pN uiil a Ctl that . ~ t i thWiinity of thu -ieof' Bisa10 . *yc ~iimyb an Adpocyte. Other iators that ray be mnanitra.-adInnhme weight~ boady ma&au Nrnd Aucoss alg l*va blcod hpid e dn nam Othado igua homefguedannuiniig ans ar conditiran dcribenl hine inatrodnctioa and eposou of a soc le' Qacid enaoding~ a siraui an AMPK osr moecuAla: than. wi reduced. the portein tevel of a sittin or MMIK ha a ceill tag. an aiRNAk. myhe accom'plished asing~ an expoasan vetor Wempiary' expnwian vecica. incude sdonovirW. netors r adenovida uaociaa vma:s ( A A. ^ A'hese~ vcr as weld~ as ohr amd anat.I&d tbr ir~nfedD vaCl < itW l aOW aUaa d1 . tIr n Aluvaa9Iv aaaat'i o d may lso<e eoducd imo- "'ells ungr lipoaaomes or similaar icebnotogio Also provdediea are ki gA :hrgeaeproe set n r moAdkTtg t accumnutioan< A kii may compiwrs our or morre agemi that ta hulmrs siatin or ANdPK prot a ctivi y tr level, e0g sittum. activaung oar inhibiutory comnpunds, such as itosa iscmribesd herein, and optiaay devices or contacting ce!!s with h aents. D ces m~ua sa rmges, stOnts and other dAevias fr matrduae a compomd into a subjec or pyi0g i aa akin 1a1= of terkisamckd kits ea diaganosing thnea kelihood of having or dJveloping wo a gain, oaitry, anusrav)rcsidtdnv, d Qhams prCtaai3013 tlarant or sCCOn'nry CntdidDas hretA ki miay cmpxase mn aget I fasrtarnfl% the tiVhy and or uptessin MM'~ of a -matuin mrAN-M Kitfor sc erring assays arm aho pided Eaempary kits cotpdse one rasa agents fbr conductag a sorsening assay su& as a auht an, MIPK or a biogcaly active ponim Mn ef. ora cE or U extttomptising s mt. Any of the kits y aho compa mnainns for use. The present descrpdon is further illustrated by the fwing e;aples. which shottld not he canstrmed a iihning in sn waisa. contunts of' si cied afrencraes (indudnglieAtureref atisud atn publenae apliu -. ndGn~n Accesion numbers as cited throughout this appicaroi) are hereby expresly iN ormtoed by fratrence.m Thm practice nf the present niethods dil mpln, ades theise hd ated, convendorianatecdm-gnes of eens bioogyeU catures maedar himie ytnsgenie Noy, adoabiioggecnhnnant DNAA*m- mai nnnoiogy 'ha are wtin the sits -of thie at Suettt mahnig are expLAnod Wiy in th iltta Se r an 4Moea ar ohaingA Lboratory anad. 2nd Ed, d by Sambrok rnwsc and M4nisaj (Cold to! H nrer1 ta te aa 91;ow DNA Cttniy Yvhmraku I ;and . (D GiovP. Mt 8 imadweovre Vyntesis (M.I ash ad, 94Tt t 48) M al.U P S ent-Not 4 553 9; Nncdk amf hbrdiadten (Bt 1 lanmes & S Hj'aa'gis ad. 19h4)i a ''nsoution And> TastdaiB H >ames & S.3 lHigginsadsI '84IVCculm Of Anian. Celi(R I . ratneuy Alan I OS 9 hunoilized Cdis And Urn.e CRM Bess, 196);4 Perba, A, Prctical GCade To Molecular ClkuIng (9%); the iusrase, ti'Mds t Enzymology (Acadrk Press, Inc,. N'2. Gene' ne :'etssm MIamalo. Cd is (S ii Mide and MI f ads ed&, 1987X Cokd Spangd iathrbo Laloatry); M etheda k nadegy, NAs 14 and 15-5 (Wmaam at PdaN hmanmm naIe Mihoxds la C&U And M.lecular Biology (Mayor and WaUkA:"e d A detl..onFt, 9i7tUmdhook Of Expenod knninoing. ?lmmnes VlV (D.M. Whir -and C. C.. Biackwd e3ads. 198 Mnipu gh Mose " ry(Cold opin Lather inaty xPesn. Cold Spang Harhor, N.Y..1986h The tigmnnrt nres for1 Exmp a y eVdi )20/036 Fx'Thw I 7Smple{~tir shows the cmound titk atvtssttis evra tmbe Ticsatufn On~vort1\ Awwat o'" t :lism b sducin fha oau an iA .. , legansi idype" '.N2 .' C lg wou wn on " 5P0 t d p oyvighti~ to vc a >~d(0, tanoi) Ane or with 10, 50 a 100 pM o1 etKaro Oa athanoit Ffat aocn \ttion Was visualize with Nile Red stiiga d'emihed nwhe bo an Ashrafi Ke at~ Nau .42.t:268.4 (2003), Theo akea i: idrs Wha 1ve6m tmn winh N00 a1 reure 2n 0.9 rduction fat acc Ouuaton Simildyt, incubin .ofthe worms in thez reone o10. ( M ot 50 pMd of resvNattO hwA a mnar'ed deease in fa iar The d me in G accumuiation i as or Inrc snriking tn tratms wnh AICAP4 a know activrhor u AMPK and fiatv acid aiatsox S' whji 4' act vated byv evratQ, &cta via tinorition factor DAF, 1.6 to p In esma, m yeast (4) wbaumad Gurae ( I Nau.rs 4?27) Simirly to het wtd4ype I. elegna zion h DAF46 m~taat wormsa .mg47< whica defetihvei mtdsnsignzahtt 'Weikow, et ol Scieneo 290:147 2000), aeao tnltsa miiationi and a Ovasm ia{j aecu:2ou Tis oateos thait rw*'ti ienabvg to IVa olism in aduk worms occos 'cia a patway that a indepiom of DAFit. Accongy, acompounds in th resventol d the d~imo atertuin praemis cen pTmote fat mohi&$ in NNth Wilddype and -a C, t. it'nauioor o irtan prctsis decrease tnt atsant a, .inditoes aa pedinsa as itleo{'mmsd shotod inaasa. tt occnnmiaridw ( ~answrms wee tarmine ovengmiatt the presce of G. I or 15 mkM inza ino d.na tains doo d an annt r ddl ontd 'EN .ei. ofira.. I in Etm w n- as on a C mle s wna inu wino t S1 was IKNA macavateid 'Toung adult woms were grown to duho in t ctena Itn cany ~RNAI vcOr alone or Vector enroding Sir2 I RNAi (R!!A8A), as eAd tow. Thas worms w r gTown in the presence or sn of resveratrol and i -Med ith lo-dRd as de so'd'ad bds The resu" s in uehmih ensetmi mbidethe t ofresvesratrot it wassn AwaNove tat Sir2 is neea ry for medasing the f'ct of rs' 7%r1 on fat me ZIWtion eis shown in this- lhampl thaAMPK ia also necssarv farmeitn fgu d s of' c MaboilX upi and fa-ty acid oxidaon Many of'pstic agnts and h ons uhaimprv .instdindsensitv t a 5,'5Onine midahz(4-4-ca boaimnrd hinJ)-beftanside (AUCM(R) and Meediomin, enttrerse 00entting nsuiin keve-I s known in tivate AM\Ph a gaung toglos upta and a acid oxidtin in mammals AMPK r e -fbes fat mrnennids by itn"t n.l fattyu and adon-a a of condstops tbat 0nVvc pi hohtyladon/ and ramno Ow tnOyT ransinw (CUT) fi 4t c by mAnnyl ,and tudpw of faytwaidswin nhe InchdA to be 011odztd WAe haxo uadd K:. CM g legns database and found two gem pznddint are Nighly related to annan A-MPNl TOOl A and 1ar23 five gens on3edinghomlogs of C~l ad oe eeenodin a homolog of COT Q eksegnoi eeiebtdws boatdra carrying RNA 4 ve-tor alone, or in .fd, RN A .iaast TOCM or F4UEZ3 a elegans homologue to COT in presence or absence ofA1C\R Fat acannMulatin was vsaneed wah NiiReasp described belowr. The .esuhiNa ndicate that NA inactivation of TOC-1 - WrinShis AICARN SiMA0ted fa nhiiadon. Thna MCARAMPK jPInK to ;ty add ox idado is voeserved in wonin and rm lan exwW The ctbot of TOC1 4 and COT inactivation was then irvestigzated in C. degans inbatd withssrnl.o CI degawns wto Ls were incuibaed with bacteria carntsing RNAI vacor *alnrt\ r a vector coding TO~t$'or COT interfrdog RNA in the presanoeo abene cfrcveratrob hataconnladiae was *.aalize wit'ier s deserbed haw. Thet rests indicate far in the presence of the RNAI vator along resrri redun-es fat content in nomia4 worms by 7$14 However RNA inaltvatn of TO P a hcoolo of mamnn-naian AMPK or F 1 4 I & a hominolog of mamntahan XOT. hn~~cks mrn esvrmtm stirmulated intmotiniwartn tints AMPIC s nssarbfo resveatri-nduced tal faU mrobilizahon Thuoa wo coucae tha.t rvave~sOl Iaaogo'Th to the~ dieuA MP ande'Or JCA(NVI Man4tesW' the sAMPE agnalin asead to *fat astabo1'ad ormso in tdonne s4 A inandvatica of DAPAQ thtr ri~naespoo factor daowndreOns of innadin signuJing to longevity or inaofdvtien of DAft16 by 02nndonh had no etrct on~ resvorntro rtnuhdo tDA 1r6,crf ""mAte It mobfi aion taggsh doi iat on of ht requin aodvati of tho AMPK sigmatng caisad to ftty PITA 4'intinon of AMP.ud COT suggeded tht the rdfoft rasVArtrol and AICAR to mobilize- fata onusi adepatder'ni*a tivadxpofthe AMFhK signanaig caseado to fatty acid oxidation. To obtain direct evidenc of AM~PK atvation. weaie whe rverntrol stuiulated ea shoannesed pofarytaw on f treoni rest, 172 in AMPfK or recoed phoborhden' ~ ~'r of do . -'toA cbofsO (ACC) at retina 7 medoittions that corrent with act-iadon of AMPk and motivadon of ACT> (ih.O11tR n aminalian cois were waboh toiPB~Iatd it rarog eaiht in na f. DMEM! hbl oreant witt500 aM AEAR (pos control, ora 5 M 25 Q or 50 PM en r CW 's W$e harveste Suer 0 nmsO and awl6tes we imnWdiAey b din SDS ad stuhjated to Wbtere ana is whh haai lie andtbodies. Phasphoryhation of ARK at Th2 indicatssrivalm o h ksas. Active AMIK The rsuo indirato phoshorylaidn of AMPK on; threonine 12 an phospnorylttin of ACC on $edt 79. T1hus, lke AICAR.. reoveratrol .ttandates phosporykntn of AMPK ad ACt hecrding, tie ability of resverarrolo biti. ft iohm pogenie suis du. ateat in par to activation ofWAMPN ignaung to faty acid oxidation C-HO callh3were als treated wi 0 gM AlAR (p1tive non DMS0'. K ft4' .. 4:2 " O ~ mvm s bx'N5 nM4 ' 12sy 2- jtrr e xt j WeAe Finr nas as deIre&d s):oe WVestem3MPot were ai' pped ae-probed kasphoryared (tetivo) AMPK, total AMPK. pheopharyated aetyl CoA embyhse (ACC). which is the I 5 dOwntroam: tartj of AMPKV an bin which seveta ledn co. Thereu show a1aaion of AMPK in C1 c10 ls with reasing concentration oflrvr§Il, Ph Ios uorhon of ACC, wMhh reecs AMPtK Sctivy. was into berved iW 3T 12 SdpAocytcs Urmsed with tr emanci or revrtrol U S cois wa incubated w"it. eihretao or~ ovverst l d thenhrete ihr 6 or 10 days aller they wer idue to di 4Zigr tis into aioytas iom the pa 3:T3 h2roblast ceti tiae, ~he rets shows ahm reavronol ilm sOd the phophoryaion of AGC St hoth dam 6 and day l AGC wME abog prsyno>dryl4 when the 2eK were mc(: atedin om teeV~A mea rveignscor hmung4t (Woae markd "SP') TYirtk It li tes O n Ith SHR ibt 5 dAy 6 is Unk1ow1 , but we hywotre tt it may e a r of SIRTE Tubuhu srved Simihri.tesults were tlse observed.for.UtP3Bi hununK hoam cells, in ti eas posphorbkiion of ACCk was measured in cells were STRT'I was overexpresosed and in calls were tsIR'T) was 1:nxkd down. Phorvlato of ACC was not ffeted iat tem teUvrwtrol may no! be wx1iun ihmugh SUCU i this ease; Ti\ served as a canwmi To further moesga whether rrol is w""adnt through SiTi, apodcy't wer e itheted wih a contrun K ) ireovin SRTI sCN A, r SR1' dommam nerative (del HY Cels were treat with AKAIR, ONthnat or entci. As deebdaove,~ coils wore harene oaind yN.tes were ropredri fr Wetsrny bt anahyes with "oA pcoao aibedices The reas 0how pophrylaion of ACC and .AMPK, whch retlects AMPK st vity >TiM otsm for ach is ann shown, N is als tual (hat to: kadting conrte CAPEiY and tlin. are exprased out a starmdy low levN in 0h0e cells and may on"y rtleet tbe presence of ndiiferendatd 3T cells. The resuhs also s ow eantldi sea rpns 't the thr right Similar resua were also obsert td in mou s mbryoni tireblst CMEPsP The rcsota show that rcsvearim!i otli has etiects in thet auec ofthe known AMhK. kmaese. MUM. CAT I th -s S o LKH], Cois in the epanel wore Inshaed ovemigh w r Sellson Oth 0'gh t ere not i te.: under $enn frtO conditionO WttItSe toading5 is W o the.:j 4 fl 2K11 . cols. XVtmtCto caurae anopegulaton Ori-i otSAWNl aOnd AV C y 'd: hrnn. Tubstint soved as a it drtng cenm r Hxwllka 6 n -. mvmk lmaddwt hkal m m-niitdm eii To Ottain aV denO tbot tieVtol aft~s fat etb U)ti isil~a re ai ed & we nioei the otine t finnsin concentS'te ot mvratraeon 2Kt4 and NUA3T3 f l difflrontiatkn and fat ontent I or N 3T3 oells wer> gcwn to ie me modnce Ind a )pwad to in hit 0 days itAih point ARantiation was initiated by ddo iot amInewtheles o dexathasor> and insao in the prcene of vehice (ot anal od ral raarat at tnn trns of 0,25 and 25 pANA Attar 10 days of> difentlnnfat content was aaeaed bOv Red O) at ning a dneondad beibe Th resultr indicate that aoncenttunt of2$ p.M s& higher reavexanaci decrate the quaantty ot cel a rtin 3 nd NHOT3 ceia T:e reano 0 NifIS MEs confAn rtbeni t cbtaitned in C adegena. The zesut indCO that reaversoni ihibts adtpipoes ( or adspor ae di fferntiawy AICAR mulates AMPK sgnaling and inibts deis in 3T3 "'' To dQdguswther the. o~ct of oxsveratrol war te inhii diftrvntiadkn or mobbac. fat trot fl~ttU X ltb astch as PPA5 e We toad at eis eoshb .n inverd did nt sho am in rease in Plky KN whicdey c ny differentation of the eais into adipocytes. ts sg~gests that besveratol i t dirente don of celsd into adinocytea. This miay also SUae thatnre itrOl inhibih "s \. Pe~ acdvity or ex<pession We ten infected 3TweoctesN Acotvtes withjMX anw or MX Anaoding
PPAR
4 nd eamined the effet of .rsvwetrol on A% ell difLerentiadnr and NII{3T3 edis were infOcted with a parmid epnag uP o AR d guzi n to COn&bninctt e Od were diicrent d 1010 adZpoI as deadbd beinw it tdei pea 0 f ii pM.., 2.: f V 50 pr tesveA. aim in whidh (etuhao. Atra ei days'f differentiation alls loc fied and stained Oil red A eapcted areapression of }PAh par uly netted ihibinon of 33 spread poyt dierunhaetivn by rsematro. This 4bsevaton sggeth at resertratinihiits Ph1>AR ttive at d dliinentiatin T* other e into whether rsaratrol nvation of sir2 om14 promote fht .nobilizatoni or inhibidon of dh nataon in meminalian cel, w ifacted powing Cdss with wis yp SYiu or a descet'4ase dhicient form of Sii i N :i cemlt we Vown in Mh presee of Virks tain GFP; S or the dcaesotae ieuALentn oR (SmtiKI desribed in et alC 20) Ce- 719491. Cda w2re ditk-e)§dated 1ak inO We PT ovvo 0pt12 resence of) dv 215 pM rnt pheesent i vethkkl (athano> l Atin eight da;ys of diffkgendadn,. eeus~wo an d and stained with 0iML.d The wsudte indicate tho.at32 CAL ha averonm WudAypn SIT 1 csho desed 149ant s cc~oard t oeie tcted with virus encoCng .01 (a necwnve con0 trC 2c 3$e ttoverexcpress th dcetylase deficient annm of STJ show an OICTOSe in tt < t smen~ TheseC :reatrontrn thefftect seen in womna hetat SiRTi acUtivtio> by es ot appran to decreasent T n m and SI inactivationt bly nicodenide appr to icrase ftA convent TIus we condlde that stains play a direct role in regulating fat cdt diethlieatimd ar id cntvt The decreasing Oil Red 0 staining see with SlIR, ovsrxpresonapproaches he evvA seen when ees oa stnimesteidf rshesveatro. 'is Observatioris the quesdN' hether the SIR T deetviaae aadcenr nntt wouid verse the ei~edef' resveratrol. W funad dat in theST1ea..dols defideWt deRAflthet d"ere5se W t at d onAy ind ocd bye rosvaS was w nded Pa y, it o uco. ThR AP henreadts intenhi in addition cut ting fOdna 1 n:iuhv.i teat otraix inhibts ae pagenedrs and that this inhibit lon is Pot. mediated last in past by SirZ VM d og.Amol fvve C.skgarst stains wer nain d as destibed a TCi3 , eet when rated ,rner) Gerneda ins The wd type referwnce strainas N i to d mutant ainuns were: stZ ir(okc44),'it t(ck5 and dat6A (NgD47). Daf+d gt7 was abadoed me thAau anrvit an other strain wre otinined :ron te Caerttrdi:f oeees Cnter (faromC Eleg~ans Gene Knockout Consortatn} hrowsth condqano anISreveratr agosore *Svgeo NGM starved ato ere oer 48 N nua ance of'hieg. enud i tg wa rechrtd. 201-I0 vog atin wonna we s \ s NKidt 2 Witi Mtg boier and OdnauIkae to newhGNO~eNiled tipedmtnei:dn phte thatoontrired either OP$0 or 141T5 c arying rhe L4440 RN'A control vetor For exspedinnts connpanng the <ffect df nicotinandeto and resvernurs on far mobilization OP$O plates were saedwith ahicle aOr or Nreotinamidein Ps, or vehiceaone and esvento n 'nol or MSO\ 1cI RN~iakte wcer seeded wit 41 1in ectryingt tithen t L44) 4NAi VCnor( io the pcsnnce: ey auence c 00 pM4 n troit Ycont itdz 'S 4 e ~re e to platt. cnnig.he appTonLC vector, kh Red a tnd g thvn dnihdedt 2$*C. Nvi Aed otadningju was assssd 24Aadn a W, atm",etrati n etN yhp Reete'o71 {iioiw 4iC12496 wef~4 dis.Ved in~ Ethanol orDMPSfO to a uM sock solhtioie. Rvekanmc uadnded to 60mm NGM sg dishes containing ethcr OPM) at R~iQA a/prsng bactermiT:) H5)to a wts conoentrton rnf.Opnr. 50mm.and I A. Nik Red was Stan addstd to platr to a fi n contentenni ofOy Q)4im hltOtfltmid Supds #478654U) was dilued in PBS including il .Red aud adskd to 60mM disth n iinOP3) toO a0 fincocwran ofili,10mMor 10 m-, M 1 lobt SiMntn Nile Redh til Red Powdrys in ANg 01> was dissolved iacetone at SOOggomi dii.d in IPWhoappass efhrd Satine (B}ining prRate dmg 11d ap(Mld to sufhont inoeadade Growth Medoa M>NOM pa s"vo md sedd with OP5 0r RNAi latonnt at a final nte"traion of (O59g at tantnas monitored and arded by Ru t so mm a'u mi0>rand AuqW hnaS aN Nile Red Sinwing w vimaliied by asngt a Nikon'. i2(0 nrowopo p -with a CY3 fikerY (ndaen 3356$nl Ig were Oca d vsing. SECYT RT aUnOchangO:&< digitaI can0a anched to tho- ikton Mioroscop- wih $KPOT RT soflwan v&Zs, A)) N11 r3 d 'a, g-ere arquire -sag ideneal atuns and *rpoa s and then changed: to red palette fA -ist town I tLeding Bata cotiing Ope-rthntai RNAI lkmes were odtood in 10mlintia iEroth medi C:OntOfaii n agn amii!n fo $or as 'nrp of ach critaro was spotted to a 6tmmI dish crudaining NOMana &nM lPl( and25gge-ti ctbenioilhn. Afte o-ndnh iba a. t maso NiL Re4 -was added on top Of 441h d o a StlCon tatinou a-,Og haang wit th . exe-aa campounds..9 oile tuning wasrassessed afhn: 4ryUVitoscoptor em'nd0oatcd ofRN 'klte tetd440 t vecO tOt 4 -kme)t was A phoype was msmigned Ony if a mndarity 0f the nimals d phenotypeMW A1 s hntpswr orm(d b esm toree aditoa. on s tes n f 3T m T3 cels wa an i I 0% cIaf senn. Mp ifenen 3T00; rcdss was perfrnid As descnbd praviolay (19v1c)ioneakion A W an awipoe My D,(9 GTaZ pomdoguatin o gee epres., du.ing.. dipPyte (tifferennitstwo. Rev, i, hm, 64, 345i7 N xIH 373 cll wAec muc touim p tud th, spa) cann KI a mb oitT no "Ida b ays (4' remet wih na ad isQuMy Wyhuthn n %fn an~s eIt drach cofluenxce, The aminking of' adipotcyna with. Oi Red'Q and qutaiaiu Wes peroredls e 're previously (amrez acaias tL Castro-Moo.$tded F. hum uN W iatochemistry, 1992 ul OW9 y Tiha armam man r vrus *p\ n vtctor pM2X (N aarihad in cntonoz t Wst (1994) (ens Deva. $:1224 Un pM ed by (Y Nan wsued w onm n p (Vaann :T al supnt and eGt. Re binat ofi pussea wtre genmrian by ..dyium h phispate nanskeV o "zorf ibe retm-n ras coshucs intn Phoema L.comypi3 c pakisg ee!!s (deS~dh ) inTilnO 0; a cSnwL a.nd provhuxd by Gary Not4ar 1 wtiad w'ererit ie in D3yti$M phs: I % ftal caf scomx, Meadia na eh9; Vthe ru sy amd vrira opentantwas harvestd twice at 4 and 22 hr posa4 tcen of packgg eens. Vra: supmaran was p1sed ibroughi :a (2 pM~' yring fie udApied to p entkent 3T342L. and. NU't3T ce~t sdfs addition ut polyhtenv to a hr3a 'cc ean of 6j pAm MedIa was4j chne the next d~ty and cel ee loe to ~ grwt cnaece fr diffensiatian w adiacyta X:amnie 5: ACd ditona s it i U~a"or3 taiolat P4 moWati (2 , T elgnWV arrswre eubased in the presence asenc 10 ipM< o4 th SIIRjTt a tivatons butei.t isets piccatann and twuere>n. and the fat cent oat the worma me 4ae as described aboe The esl indicate that inese Sk i actntx have a .d3oI4at :oifltc 5ix .>yado, iy' 1 r0Phi'i fl(4tjhtli?t4 Ft1Ilkm'iNee gh4 ~ed k and tiseths redu~ca (Pu accumu lika at cocnmsn aslwa ntdp.
C' legas worms wo> inct bated irt t ance~ 0% v/v DM3O) or preswn oft MVI 34-d2 h 4iro):v4Ahiarmethl vi~ntijbtene for 24 hours, Sinnc reductions ot tYit staim by~ i Gdiby 4ta'othylbMtrans ilbene was &ban Ayinma in we e also iuadni amece '25 % nov'M or presen, of 100 1 t1 vsratrol or 9 ( M ct4' n tr 4$ .ouls. Sigmcart rumtion oft s mAintig by ravrao Us caompared to 1he azmitl, '"at accennvt~ Ion was vni sned with Nt:. Read a hpphtinc tin :d: od. in AshT~dl .t x1 , o m for.80. hisp enrpie o s that rer xTl tnsulld soio'n ya oan t Adiocyeswoe trete with TNt-'apha 'i aduc irnsuli tkestanc e: dewart!z m Kab~aama et a, Gytiology 15:2129 Kand Wu et Moi, Cei .7":N514 0999 T'r mn wit rozighitazone, a pot'dtv controL .naacrssthe up ne of radiativet uo mdicayadug mncreased insii son"stivity of the YT $Iph treated 5dipocyVers Tresttmet with 5 gtM or 15 gM tesverattoi patvl rescued the 'I1Karla threat %dipocyes rtoring insulin sensitivity in the ~trte ctlh IThe reuisso thedesre etfve of iriereased now R m : o Mgtepi aks ~is is the ma or haonxe chgdt ith pomotingt stom to exc~ess energy ats tic. In cells wi Iipogetnc rspcity, insli hs signing promotes faI deposition When nu stores become exssive tIs process hr refrred to as dyalipgnes. Dxionss i assaed with insuln reasttnce and~ the progressive toncase in cicltn isl riglyedswLvls propenity to ypresion and atertclers& that is characteist 'f metaboahe syndrome [MuoierjAt.and. D, and 3. .Kotake SJRB- aee gulatory k o synome X29 AnnN Y Acad S.I, 2012. 97: p. 19-2Y. invulTh smiizes such as AICAR AmIStoD-ribofimmnsidl and metnomn aanivate AMFP k ar ad owbibz fo o on *condipno cela threby 5ducing immih.0 nai c and Sciirm lipid edo [Un, 5LZ. et a, Mettrt n ve yiver disea in obese. epti defiient mike Nat M kd, 2000 ) 6p 998.1003; Beo R, t a0: ENot mi ae-aomie taMDrib> dgndu inftiion cn in vivou gaoun and lipid mdn toaim in lea and sos ker asiabets 200.50(5) p.it?&2{ Anipie dexists thadt poi4tphenllw campounds derived nom wine rdue seme lipel and~ athk oscirotwic pe~ [Waddizngl., }& I.E Phddey. nd K+D. t.C:i Red wina ppno*P- nepnundb ihit athe(vilmst in~ a p gogroeid E de elt nuce OAeened of edet on bipjd 1 >emata. Am . Td n 2004.. 9(1p n mIj Our tbevaian that reeveretiml aetivetes AMP kiase suggest that tie drag rana eoue AICAR tied vi atbrnN ' he le ini ratin dysgeh esi cand i iatn mneuai sensitiviy A piusthoa OX poti ienite that AltAR end me ihuia tcate AdIPIC which in tm ph shorlaia d inhtbli eeelenA catharyVRSC (ACC) (teiews by Knp, BE~ et ala'aingt who nrgy deand the A\Muedvai etdnes imtst Tfrpads 1cm Ski. 199% 24(14 p- 222d 1emp, BE. e at AMP a dvated prehadenst, super nen o~i - A&t n IAN rgulat. Bii wheiao S Tmnt 2003. 31(Pt if pn '2 ,a V :t aL, The *AM aetivated prateik ahmseupha catdrnic sunat controls whdce-bedy in seu nsivin'y i Ch Iia3. 003i. tr p 91 MV AVIl. B. e a:.hyeioke k mof M4aetivated rot4in Uinase (MPKQ nighte IOmf nea at mucse models.Biochenda : lema 2r00s 31 1 1): p 21601 udemnan. N et,4 lsany'- ue sensin and lasuni maistane A J, tnaiot 199, 276(1 St ipB1434$; Mun IER, Ba and MU Beha e<ai anpin AMiacndated pvedin km'nse in sketel mustice: update tie la ynied Bi&he Sue Tran, 2003. 31>P) p 22 4, and Zhoi 0 et aI, Role of AMTP-eNvOtd prot Kinma, in sPWv Oauntretu nn ted\nj in n , 2001 1(& p11677 4) beenadi CC has the dual r f nOMn down n Af bisyuhisand rleasig .ifaty acid Itraes caaitie-pahnatoyl misf ased (CPiTM4 and eamihine manlopiy<" !asfere (~
T
) front end product i by nldonyl A Ma a40u M14o, dt idendioo of the two hietidie residues iespnse for the nhibion b1maIOnyi-COA in persaxisonia caitine octaMnvYlasens e fron rat liver. P5135 Put 2000. 46&(i p ~. 14 The.11 mnehis deasased de na(3 at ieaan and increased dmty acid cixidadion FA with a consequent deemse t ellular ft esntntut Hving shown that re N pnof AM Win nd AC we cmna that )v-ntroj d C p o n kom rnitate n two hean ia ceillines (Tabie i uhe ri o 6~ tbid inercase in CO 1 production nmies It sinmuhe achieved ~ 1h wit Mmimi s m" or datan suggests, thaeve i cania ae nil" pmxndh- iY 'P konyxA ht vterv ntihubas Oe f CAv on Wobotata don da& fl t biosynthcsia and ethnul fatty acid oxidation. tblin Re ) ntswcratro ik othor AMBii'acdvaters cas timuate~ fatny acid u~dXio (xid tof "S t;tknow in hptoia ce inatied with vh s U1enr (I oDMSO H2CO at appxopdatzjgezat&a ( M10 in I% i.dO) ACAR (500 M in HO) or medtin(intt fbrg 4 h4at aseibed i Mathodat.Te foa ?tefcUIt teseraraon C roduXo shw 14C4 - auee (C a~i~ ella-x Ml? it Modnn dat. on. f .p .... o .d ......... ( i ..... [Wide ILAad BE Kenp Inulinactivation 0f ac't CroAcrbylsnapod hr inhibitionoftte AMavated protein :anase lholthtem 1i02 267) p. .2&i4-7 ad HepiO2 caets ier 'nmi~nond as describnt above' C"tc{ 16 cells/iI24wore eeded in a T25 thank one day pron to the expennnt On the daavnt the or ntrent ccaps ore washed Win ansay btd (114 miNiaO4 A A'M 2m~"I Xi edvu N MgSOA it mnM seseheore iaheling. with 4Capalmitate (0.A p~h)iend pence of vehicle, or 'Ame' 10 eXMt.or AICQAR ($0 ~tfor 4 hoore Ar he cnd of incubaorste cap of achk12 flask was repaoed with a tnppner and anI' " W ~\hatman ikhen ipar noaked with 250 nd "M aG h'- fanhk was jeted wath "i nd of 6N IC phce in00 alozna olinfr1 iue n Rsanding 0V01m1g2t the aiOXtmPcar~n ad HIfl ad 61 piiNaO$. wore added to) ai giatt tcntii%&tn vitl and the fi.ter piapers forn each:* s Ra tk wer r anv td their naedevian. I nil qknsoi wasaded to each vial and allowed to stand for 2>~ hours after whicihne via were vortexed to dissive the N&C 4 COs and counted ia the acint 1:o ~ctkI onrter The resuitt were exipressed an onolh/Iiti onts and shown as the ald tzI7hct C~ t aede ranged Ihomi(2 3 . in oIndh/hh06 eblirPe a-peinent.as repeated dure es 1 213 2 49z 7 3oneyear old~ mice wore subjeced onopfire. dil~hat di-etsa catad reaudkted diet Cbt:andd ouEAt) diet or Weer~highft dij ee k n ke C. .t Med of aloc t of the AL doet h m r eRxeir u or $0 igday of r nsve-arno, 10J nd 400 mgfkg of feed/dat At 18UI nths adeos mea t 'remet wee madek in the uC Measumment of dwe Senm glicaaleveia. ndatd tt tml owers d a enun glu-ose levels in At ad reeaat diet fd mice and this abuen in e i sthm 'and a Wtats inoe 22 A nd Asanvis of tch' liver Sated thatwestern diet fd ic had a i:w WtWmuch bigger (m least about twice as g as that -of nice on a law hit diet SignitiantW mice on a Wstamrn diet that r eived daiiy does of r esvatxal had a lver that was the size of that of the low- ft dieonmrolhne Oil Red O t stab ofirmeod the presence of high fat in the 1ier, of stem-N diet fed ne. On die contrary, the at content of4he leta of ud on a Wasern dietthat receved daily doses of t w im r to that of the Ow ft diet Atchn - of their inedirs aetivay in, the ie. by m~aanig theleveof iaul in aaurn aa toes stiler ehiwa:adadxiatiun indicated that the wire VMS a adminisadon of resveratA to the mice on a Westera diet maintained theirinsan itivtt-- (gre 22 ]n, addto Si ove a'Ti ngransgenic mice also have a lower its mins level reisive to wldaypet inaenii ng dat th i rigof5sui levels by rsveratl iN likey to be tlioagh SIRTI activadan These expe mesa oh showed that resveratexiend f0the1o, Mt etaistrngeat v40 thei revwnso doseii these p Himens fQA palts'M of AN-93 ad ed detws preparetd and shipped aier vaconi every six 1oiad by Raeseh Diwts (Ne w Brunsw ik. R . gond wsa prepared under lo i 5 5 - --- yl-hthe seared under estrogen ard stored v 00 "C Fotrampl- t3 wecks. the ee rsar:ival of oice tht ere not tede with rerverCCC as abcoun ?'% wh-eres itwas about $IQ% and WO hor nues reecivhn abou L-g- of uvadav and cbout 50r g of mt$dagVofas-eratrol daily rsctse- y 5Z 174

Claims (2)

11. The ttt ofdaim 1, catalate otmpimn angnt hav fornlt la[. The tase of cltan (41ther QcompaNsng adinntado a dhe subjct a t agent that (i) creases the actihvy or prtn eel ''' saa cermnan a edi; uoereaaaa the activity orprteha kvel raf 5 AMP-sckettedpoti haid kase(AMK) in a el~;trit an anIke ait $rngA' 8. Theuse of *-en 2 eain the sc a ernds an anti-ohesii agent, . Uwe C a compound of tatm ai er 940 for the preparadeon of a inediunen for oning weight gai in a. subject indeed thereft 19 TheL '~ det cfhtim 9 frther comparidae lduniiaerag to the iate fa second e'.dt 1. The use o in 10;wherein the second agent is a weight gain 1=nmoting. agent 2L The use of crain a, whradesbe a hiina 1 . The e oft dan IQ rin the .sahjet an hAipian 14The use otc at hereint the siihjedadhaata.e 1$. Use of a nomprund of ftsndca 23~4 .' 54-4 91 or A for the preparation of a meiarsnrtfh evttyntingftgeaoutkaino ia a ell wit hapronc aity I. Useof a copund of krannt 48>51. $33-r 8890 tea Wanpreparation of a .raadcant Oa thaactig ftt accauaion in ot~Pttr pgenesisot fa c l?. ahe use of cgt~n it whwerin the cn with npogenic aaaw isa ayr. nettes or rnsele cet. .18 The are of timt lIwhereinthe1 r"'is adipocyte. 19, U<o f acmmntcn-ud of toznnila 48-521, "' S k o 8r 9 he pr- Pawtcion a rincnalld for pravoatlng Me diilhv iaiio of a aaqy, owog
20. "iMs taf of' ~im 1, \t "m icl -,Wo
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