
selective eastrogen receptor modulator

selective eastrogen receptor modulatorlu (serms), eastrogen receptor agonist/antagonists (eraa) anie kooda pilustaaru, ivi eastrogen receptor (err) paie panichese aushadhaala taragati. eee padaarthaalanu swachchamaina err agonistlu mariyu satruvula (antey, puurti agonistlu mariyu nissabda satruvulu) nundi vaeru chese lakshanam emitante, vaati charya vividha kanajaalaalo bhinnamgaa untundi, tadwara vividha kanajaalaalo eastrogen lanty charyanu empikagaa nirodhinche ledhaa prerepinche avakaasaanni istundi.
vaidya upayogaalu.
vandhyatva nirvahanalo andotsargamu panicheyakapovadam, rutukramam aagipoyina bolu emukala vyaadhi chikitsa mariyu nivaarana, rommu cancer pramaadaanni tagginchadam mariyu tagginchadam mariyu rutuvirati kaaranamgaa diasperania chikitsato sahaa vividha eastrogen-sambandhita vyaadhulaku serms upayoginchabadataayi. eastrogen lopam lakshanaala chikitsa kosam suuchimchabadina samyojita eestrojenlatho mariyu ruthuvirathiki sambandhinchina vasomotor lakshanaalatoo kalipi kooda sermnu upayogistaaru. vividha kanajaalaalo vaati charya namuunaanu batti serms upayoginchabadataayih
tamoxifen anedi err-positive metastatic rommu cancerku modati-varusa harmonela chikitsa. idhi adhika pramaadam unna mahilallo rommu cancer pramaadaanni tagginchadaaniki mariyu accellary node-negative mariyu node-positive, ductal carcinoma "inn situ" yokka sahayaka chikitsagaa upayoginchabadutundi. rutukramam aagipoyina mahilallo emuka saandrata mariyu rakta lipidla chikitsalo kooda tamoxifen chikitsa upayogapadutundi. pratikuula prabhavalalo hott flushlu untaayi mariyu vayassu-saripolina janabha unna mahilalatho poliste endometrial cancer vachhe pramaadam rendu nundi moodu retlu ekkuva.
chlorinated tamoxifen utpannamaina toramifine, preclinical adhyayanaalalo tamoxifen thoo kanipinche daanikante kaaleyamlo takkuva dna jodimpulanu kaligistundi mariyu hepatic carcinomas nivaarinchadaaniki abhivruddhi cheyabadindi. idhi err/pr-positive dasha 4 ledhaa punaraavruta metastatic rommu cancer unna mahilallo endocrine therapyga upayoginchabadutundi mariyu rommu cancerku sahayaka chikitsagaa mariyu metastatic rommu cancer chikitsalo tamoxifento poliste idhe vidhamaina saamarthyaanni pradarsinchindi.
bolu emukala vyaadhi unna adhika pramaadam unna rutukramam aagipoyina mahilallo rutukramam aagipoyina bolu emukala vyaadhi nivaarana mariyu chikitsa mariyu rommu cancer nivaarana kosam raloxifane upayoginchabadutundi. bolu emukala vyaadhi chikitsalo eastrogen kante idhi chaalaa takkuva saktini kaligi untundani preclinical mariyu clinical nivedikalu suuchistunnaayi. idhi aamodayogyamaina endometrial profiletho mudipadi untundi mariyu garbhaasayamlo tamoxifen lanty prabhavalanu pradarsinchaledu, conny sirala thromboembolism mariyu hott flushlatho sahaa vasomotor lakshanaalu vanti pratikuula prabhaavaalato mudipadi undhi.
aspemiphene anedi toremiphene yokka saaruupya metabolite. tamoxifen maadirigaa kakunda, toramifane eluka hepatocarcinogen kaadu, anduvalla tamoxifen kante aspemiphane kooda surakshitamaina serm avutundi. idhi rutuvirati thoo sambandham unna vulver mariyu yoni ksheenata yokka lakshanam ayina mitamaina nundi teevramaina dysperania chikitsa kosam upayoginchabadutundi. rommu cancerpy clinical dayta andubaatulo ledhu, conny inn vitro mariyu inn vivo dayta rendoo rommu kanajaalamlo aspemiphane chemopreventive charyanu kaligi undavacchani suuchistunnaayi.
rutukramam aagipoyina mahilallo bolu emukala vyaadhiki chikitsagaa bajedoxifine nuu upayogistaaru, idhi pagulu vachhe pramaadam ekkuvagaa untundi. idhi saapekshamgaa surakshitamainadi mariyu baga sahinchadaginadigaa choopabadindi. idhi rommu ledhaa endometrial uddeepananu choopinchadu mariyu modati rendu samvatsaraalalo, sirala thromboembolismlo chinna perugudala manchidi, mariyu deerghakaalamlo itara sermla maadirigaane untundi. raloxifane kante bajedoxifane yokka prayojanam emitante idhi endothelial naitrik oxide synthase charyanu penchutundi mariyu vasomotor lakshanaalapai 17β-estradiol prabhavanni vyatirekinchadu.
modati kanajaala empika eastrogen complexes (tsec) samyugmita eestrojenlanu mariyu serm bajedoxifine vaati karyakalapalanu militam cheyadaaniki militam chestundi. eee kalayika chikitsanu ruthuvirathiki sambandhinchina mitamaina nundi teevramaina vasomotor lakshanaala chikitsalo, rutuvirati aagipoyina bolu emukala vyaadhi nivaaranaloo alaage garbhasaya tolagimpu kaani rutuvirati tarvaata mahilallo eastrogen lopam lakshanaala chikitsalo upayogistaaru. eee kalayika endometrium yokka eestrogenik prerana lekunda vasomotor lakshanaala upasamanaaniki sambandhinchi eastrogen prayojanaalanu anumatistundi.
aushadha shaastram.
pharmacodynamics.
serms anevi err yokka pootii pakshika agonistlu. vividha kanajaalaalu endogenous eestrojenla charyaku vividha sthaayilalo sunnitatvaanni kaligi untaayi, kabatti sermlu eestrogenik ledhaa anty eestrogenik prabhavalanu utpatti chestaayi, idhi prasnalooni nirdishta kanajaalam alaage serm yokka antargata charya (iaa) saataanni batti untundi. adhika iaa mariyu ekkuvagaa eestrogenik prabhavalu kaligina sermku udaaharana chlorotrianisin, ayithe takkuva iaa unna sermku udaaharana mariyu anduvalla ekkuvagaa eestrogenik vyatiraeka prabhavalu ethamoxytriphatol. chlomiphane mariyu tamoxifen vanti serms vaati iaa mariyu eestrogenik mariyu anty eestrogenik karyakalapala samatulyatalo madhyalo untaayi. raloxifen anedi tamoxifen kante ekkuva eestrogenik-vyatiraekamaina serm; rendoo emukalo eestrogenik, conny raloxifen garbhasayam loe eestrogenik-vyatiraekam, ayithe tamoxifen sariiramlooni eee bhaagamlo eestrogenik.
binding sait.
eastrogen graahakampai serm charya (er), idhi kanaantara, ligand-aadhaarita transcriptional activator mariyu nuclear grahaka kutumbaaniki chendinadi. era yokka rendu ververu upa rakalu gurtinchabaddaayi, era mariyu erbita. eastrogen sankethaalu transcriptional sthaayilo prasaram cheyabade pradhana maadhyamgaa era pariganinchabadutundi mariyu stree punarutpatti maargam mariyu ksheerada grandhulalo pradhaanamainadi, ayithe erbita pradhanamgaa vascular endothelial kanaalu, emuka mariyu maga prostate kanajaalamlo untundi. era mariyu erbita ekagrata anedi abhivruddhi, vruddhaapyam ledhaa vyaadhi sthithi samayamlo kanajaalaalo bhinnamgaa untaayi. parimaanam (~ 600 mariyu 530 amaino aamlalu) mariyu nirmaanam vanti eee rendu rakaala madhya aneka lakshanaalu okela untaayi. dna-binding domainlo amaino-assid sequence identitylo sumaru 97 saatam mariyu ligand-binding domainlo 56 saatam share chestaayi. ligand-binding domainla yokka pradhana vyatyaasam liu-384 mariyu erlo mett-421 dwara nirnayinchabadutundi, ivi erbitaalo varusaga mett-336 mariyu ail-373 dwara bharti cheyabadataayi. era mariyu erbita madhya enn-terminuslo vyatyaasam ekkuvagaa untundi.
dna-binding domine rendu upa domainlanu kaligi untundi. okati dna gurtimpulo palgone sameepa pettetho, marokati dna-aadhaarita, dna-binding domine dimerisationku baadhyata vahinche dhoora pettenu kaligi untundi. sameepa pette kramam erα mariyu erβ madhya okela untundi, idhi rendu upa samuuhaala madhya saaruupya vishishtata mariyu anubandhaanni suuchistumdi. dna-binding domine yokka globular proteins enimidi systeinlanu kaligi untaayi mariyu rendu jink ayanla tetrahedral samanvayaanni anumatistaayi. eee samanvayam eastrogen pratispandana muulakaalaku err yokka bandham saadhyam chestundi. ligand-binding domine anedi 11 helixlatho tayaaru cheyabadina golaakaara, moodu porala nirmaanam mariyu sahaja ledhaa synthetic ligand kosam oka paaketnu kaligi untundi. bandham anubandhaaniki prabhaavitam chese karakalu pradhanamgaa final bhaagam, paramaanu parimaanam mariyu aakaram, dwandwa bandhaalu mariyu hydrophobicity undatam.
ligand-binding domainlo ligand-binding ligand dwara activating function 2 (af-2) helix 12 yokka differential positioning ligand agonistic mariyu vyatiraeka prabhavanni kaligi undho ledho nirnayistundi. agonist-bound grahakaalalo, helix 12 helix 3 mariyu 5 prakkane unchabadutundi. helix 3,5 mariyu 12 kalisi canonical sequence lxxll (ikkada l anedi lucine ledhaa isolucin nuu suuchistumdi mariyu x anedi edainaa amaino aamlam) thoo cooctivatorlaloo unna nr baaks motifku binding uparitalaanni yerparustaayi. antagonist ligandlaku kattubadi unna unliganded (eah. pii. oo) grahakaalu ledhaa grahakaalu helix 12nii lxxl-binding uparitalam nundi dhooramgaa maarustaayi, idhi corpressorlu enn. sii. aarr. 1 ledhaa ess. emm. aarr. tii. paie unde podavaina lucine-ritch motifku, lxxxx (ii/ell) yokka preferential binding kii daariteestundi. adanamgaa, konni cofactorlu terminals, dna-binding sait ledhaa itara binding saitla dwara ertho bandhistaayi. anduvalla, oka sammelanam cooctivatorlu samruddhiga unna kanajaalamlo err agonist kaavacchu, conny corpressorlu samruddhiga unna kanajaalaalo err virodhi kaavacchu.
charya yokka yantraangam.
eestrogenik sammelanaalu krindi vaati nundi karyakalapala yokka varnapataanni kaligi untayih
serms kaaleyam, emuka mariyu hridayanaala vyavastha vanti kanajaalaalo eestrogenik charyalanu prerepistaayi, conny rommu mariyu garbhasayam vanti uddeepana kavalsina chota eastrogen charyanu nirodhistaayi. eee vedana ledhaa vyatiraeka charya grahakaalalo vividha nirmaanaatmaka maarpulaku kaaranamavutundi, dheeni phalitamgaa eastrogen lakshya janyuvula kriyaaseelata ledhaa anachivetaku daariteestundi. serms kanaalaloki vyaapti chendadam dwara graahakaalato sankarshana chendutaayi mariyu akkada era ledhaa erbita upabhaagaalato bandhinchabadataayi, dheeni phalitamgaa graahakaala dimerisation mariyu nirmaanaatmaka maarpulu jarugutaayi. idhi eastrogen pratispandana muulakaalatoe sermlu sankarshana chendadaanni sulabhataram chestundi, idhi eastrogen-inducible janyuvula kriyaaseelataku mariyu eastrogen prabhaavaalaku madhyavartitvam cheyadaaniki daariteestundi.
serms yokka pratyeka lakshanam vaati kanajaalam mariyu kana-empika charya. nirdishta rakaala kanajaalaalu mariyu kanaalalo janyuvulanu lakshyamgaa chesukovadaniki corpressorlu mariyu coactivatorlanu enchukovadam dwara serm karyakalapalu pradhanamgaa nirnayinchabadataayani maddatu ivvadaaniki aadharalu perugutunnaayi. serms coactivator protein sthirathvaanni prabhaavitam cheyagalavu mariyu phosphorylation vanti anuvaadaanantara maarpula dwara coactivator karyakalapalanu kooda niyantrinchagalavu. eastrogen vyatiraeka chikitsaku pratispandanagaa herr2, pikesi, paie3keey mariyu marinni vanti bahula vruddhi sankethaala margalu tagginchabadataayi. steroid receptor coactivator 3 (src-3) anedi daani coactivator kaaryaacharananu merugupariche, kanaala perugudalanu prabhaavitam chese mariyu chivariki aushadha nirodhakataku dohadapade activated kinesla dwara phosphorylated cheyabadutundi.
lakshya sthalamlo erα mariyu erβ nishpatti anedi serm karyakalapalanu nirnayinche maroka maargam kaavacchu. adhika sthaayi cellular vistarana adhika erh erbita nishpattitoe baga sambandham kaligi untundi, ayithe cellular vistarana yokka anachiveta erbita erapy aadhipatyam chelaayinchadamtho sambandham kaligi untundi. sermsto chemoprevention parigananaloki teesukunnappudu neoplastic mariyu saadhaarana rommu kanajaalamlo ers nishpatti mukhyamainadi kaavacchu.
era mariyu erbita madhya thedaalanu chusinappudu, function 1 (af-1) mariyu af-2lanu sakriyam cheyadam mukhyam. janyu pratilekhanaanni niyantrinche itara saha-niyantrana proteinlatho paraspara charyalo avi kalisi mukhyamaina paatra poeshistaayi. af-1 err yokka amaino terminuslo undhi mariyu era mariyu erbitaalo kevalam 20 saatam homologus matrame. marovaipu, af-2 anedi era mariyu erbitaalo chaalaa pooli untundi, mariyu oka amaino aamlam matrame bhinnamgaa untundi. era mariyu erbitaalo af-1 praantaalanu marchadam dwara, transcription karyakalapalalo nirdishta thedaalu unnayani adhyayanalu choopinchaayi. saadhaaranamgaa, eastrogen grahaka moolakam dwara eerae dwara injaneerd janyuvulanu serms paakshikamgaa sakriyam cheyagalavu, conny erbita dwara kaadu. ayinappatikee, raloxifane mariyu tamoxifen yokka kriyaaseela roopam era mariyu erbita rendintiloonuu af-1-niyantrita reporter janyuvulanu prerepinchagalavu.
rendu upa rakalu unnayani kanugonnanduna, idhi oka nirdishta grahakanni aann ledhaa off cheyagala grahaka nirdishta ligandla shreni samshlaeshanhanu teesukuvacchindi. ayithe, phalitamgaa vachhe sanklishtata yokka bahya aakaram kanajaala lakshyam vadda pratispandananu sermku maarchadaaniki utprerakamgaa maarutundi.
eestrojenlu ledhaa antieestrojenla ex-rae sphaticalography ligandlu itara proteinlatho sankarshana chendadaaniki grahaka samudaayaanni elaa programme chestayo choopinchindi. eastrogen ledhaa anty eastrogen complexes aakaram aadhaaramgaa ligandlu coactivator bindingnu elaa prothsahistaayo mariyu nirodhistaayo err yokka ligand-binding domine pradarsistundi. ertho bandhinche ligandla vistruta shreni oka nirdishta lakshya pradaesamloe puurtigaa eestrogenik ledhaa anty eestrogenik ayina err complexela varnapataanni srushtinchagaladu. ligand-binding yokka pradhana phalitam ligand-binding paaket yokka nirmaanaatmaka punarvyavastheekarana, pradhanamgaa sii-terminal praantamlooni af-2 loe. ligandlanu erku bandhinchadam anedi cofactors mariyu receptor pharmacologyni niyantrinche hydrophobic paaket erpadataaniki daariteestundi. ligand-binding domine yokka saraina madata transcription yokka kriyaaseelataku mariyu aneka coactivatorlatho sankarshana chendadaaniki avasaram.
coactivatorlu anevi kevalam oka samudaayamlo saitlanu anusandhaaninche protein bhaagaswaamulu matrame kaadu. complexes yokka kaaryaacharananu savarinchadamlo coactivatorlu churukaina paatra poeshistaayi. coactivatorla yokka anuvaadaanantara savarana kana uparitala vruddhi karakam graahakaalache praarambhinchabadina bahula kines maargaala dwara steroid harmon charya yokka dynamic namuunaaku daariteestundi. oka nirdishta janyu prothsaahaka pradaesamloe phosphorylated ertho sankarshana chendagala bahula protein coactivator complexenu roopondinchadaaniki aneka protein punarnirmaanaala maargadarsakatvamlo, core coactivator modata nirdishta cocoactivatorlanu niyaminchaali. core coactivator core coactivated complexga sameekarinche proteins methylate ledhaa acetylate prakkane unna proteinlaku vyaktigata enzymatic karyakalapalanu kaligi untaayi. praticharya yokka bahula chakraala dwara err uparitalaalu ledhaa kmjime eah nuu polyubiquitinate cheyavachu ledhaa, anusandhaana proteinlanu batti, vaatini marinta sakriyam cheyavachu ledhaa 26la proteasome dwara adhokaranam cheyavachu.
tatphalitamgaa, err mariyu coactivatorla yokka nirmaanam mariyu phosphorylation sthithi dwara programme cheyabadina mariyu lakshyamgaa unna samarthavanthamaina janyu transcription kaligi undataaniki, transcriptional assembly kosam punarnirmaana saamarthyam yokka dynamic mariyu chakriya prakriyanu kaligi undaali, aaa taruvaata transcription complexes protesome dwara takshaname naasanam cheyabadutundi.
nirmaanam mariyu paniteeru.
nirmaanam-kaaryaacharana sambandhaalu.
serms yokka pradhana nirmaanam 17β-estradiol templetnu anukaristundi. avi 1-3 anuvulatho vaeru cheyabadina rendu sugandha valayalanu kaligi untaayi (tarachugaa oka stillbean-rakam amarika). korloni rendu phenyls madhya, serms saadhaaranamgaa 4-pratyaamnaaya phenyl samuuhaanni kaligi untaayi, idhi err kuu kattubadi unnappudu, estratrien nucleus sthaanam nundi project chestundi, tadwara helix 12 receptor opening nundi kadulutundi mariyu coactivator proteins saadhaaranamgaa err agonist karyakalapalanu kaliginche sthalaanni nirodhistundi. serms yokka pradhana bhaagamlo chaalaa vaividhyaalu unnaayi, ayithe side chainlo thattukogalige daanitoe takkuva vasyata undhi. sermlanu vaati pradhana nirmaanam dwara vargeekarinchavachhu.
modati taram triphenylathylenes.
nivedinchabadina serm-rakam anuvula modati pradhana nirmaana taragati triphenylathylene. stillbean core (naan steroid eastrogen, diethylstillbestrall maadirigaane) tappanisarigaa 17β-estradiol vanti steroid eestrojenlanu anukaristundi, ayithe side chain steroid nucleus yokka 11va sthaanamtho ativyaapti chendutundi. triphenylithylene utpannaalu ethylene vantena samuuhaaniki jodinchina adanapu phenyl samuuhaanni kaligi untaayi. finals yokka 3-position hetch-bandham saamarthyam anedi err binding kosam mukhyamaina avasaram. 
modati aushadham, chlomiphine, ethylene side chainpai chloro-pratyaamnaayaanni kaligi untundi, idhi taruvaata kanugonna aushadham tamoxifen maadirigaane binding anubandhaanni utpatti chestundi. chlomiphine anedi eestrogenik (sis-roopam) mariyu anty eestrogenik isomerla (trans-roopam) misramam. sis mariyu trans rendu pratyaamnaayam kaani phenyl valayala yokka rekhaganita sambandhaala paramgaa nirvachinchabaddaayi. chlomiphane yokka rendu isomerlu ververu profilenu kaligi untaayi, ikkada trans-roopam tamoxifen maadirigaane kaaryaacharananu kaligi untundi, ayithe sis-roopam 17β-estradiol laaga pravartistundi. trans kante sis daadaapu padhi retlu ekkuva saktivantamainadi. ayithe, trans isomer anedi epithelial sell hypertrophieki atyanta saktivantamaina uddeepana, endukante chlomiphane takkuva motaadulo vyatiraekamainadi mariyu adhika motaadulo agonisticga untundi. vyatiraeka isomerlu garbhasayam mariyu ksheerada cancerlalo nirodhaka eestrogenik prabhavalanu kaliginchavacchu, ayithe eestrogenik isomer emukalo eastrogen lanty prabhavalanu utpatti cheyadaaniki kotta graahakaalato kalapavacchu.
harmon-pratispandinche rommu cancer yokka anni dasalato badhapaduthunna mahilalaku, antey, rommu cancer, idhi err mariyu/ledhaa progesterone positive rendintitho badhapaduthunna mahilalaku tamoxifen empika chese chikitsagaa maarindi. americalo, rommu cancerku adhika pramaadamgaa gurtinchabadina mahilallo roganirodhaka chemoprevention kosam kooda dheenini nirvahistaaru. tamoxifen anedi swachchamaina anty eestrogenik trans-isomer mariyu sareeram antataa eastrogen lakshya kanajaalaala vadda avakalana charyalanu kaligi untundi. tamoxifen rommulo empika chesina anty eestrogenik, conny emukalu mariyu endometrial cancerlo eastrogen laantidi. microsomal cytochrome pii450 (saip) enjaimla dwara tamoxifen kaaleyamlo modati dasha jeevakriyaku lonavutundi. tamoxifen yokka pradhana gvakriyalu "enn"-desmithyltamoxifen mariyu 4-hydroxytamoxifen.
4-hydroxytamoxifen yokka spatikaakaara nirmaanam ligand-binding domainloni err yokka amaino aamlaalatoe sankarshana chendutundi. graheetalooni phenolic samuuham, neeti anuvu, glutamate mariyu arjinin (era; gloo 353/arg 394) madhya sambandham adhika anubandhaanni bandhinchadamlo parishkaristundi, tadwara 17β-estradiol yokka valayanni pooli unde phenolic valayamtho 4-hydroxy tamoxifen, final laeni tamoxifen kante 100 retlu ekkuva saapeksha bandham kaligi untundi. daani oo group tolaginchabadithe ledhaa daani sthaanam maarchabadithe binding anubandham taggutundi.
tamoxifen ertho bandhinchadaaniki triphenylethylene bhaagam mariyu side chain avasaram, ayithe 4-hydroxytamoxifen kosam, side chain mariyu phenyl-propean ertho bandhinchadaaniki keelakamaina nirmaana mulakaalugaa kanipinchavu. side chain yokka basic mariyu podavu tamoxifen yokka ertho bandham ledhaa tamoxifen yokka β-ring kosam keelaka paatra pooshinchinatlu anipinchadu, conny tamoxifen yokka stillbean bhaagam ertho bandhinchadaaniki avasaram. 4-hydroxytamoxifen yokka err binding kosam hydroxyl group pratyeka praamukhyata kaligi untundi, mariyu tamoxifen yokka eethail side chain err yokka ligand-binding domine nundi bayataku podustundi.
kontamandi tamoxifen viniyogadaarulu garbhasaya cancer, hott flushlu mariyu thromboembolisms raetlu penchaaru. eee aushadham elukalalo hepatocarcinomacu kooda kaaranam kaavacchu. idhi bahusha tamoxifen stillbean core yokka eethail samuuham valla kaavacchu, idhi dna alcalation mariyu strand skishanku kaaranamayye allilic aakseekarana kriyaaseelataku lobadi untundi. eee samasya taruvaata toramifinelo saricheyabadutundi. tamoxifen anedi lakshya pradaesaalaloo raloxifen kante ekkuva swachchandamgaa untundi, endukante espi-351 looni err yokka amaino aamlam mariyu serm yokka antiestrogenic side chain madhya sambandham undhi. tamoxifen kosam side chain espi-351 nuu tatastheekarinchadu, kabatti sait err yokka sameepa chivaralo af-1 nuu alostericalga prabhaavitam chestundi. eee samasya rendava taram aushadham raloxifinetho sarididdabadutundi.
toramifine anedi steroid kaani triphenylithylene antiestrogen tamoxifen yokka chlorinated utpannam, idhi ethylene side chain vadda chloro pratyaamnaayamtho tamoxifen maadirigaane binding anubandhaanni utpatti chestundi. toramifane yokka nirmaanam mariyu kaaryaacharana sambandham tamoxifen maadirigaane untundi, ayithe idhi dna alcalationku sambandhinchi paatha aushadham nundi gananeeyamaina merugudalanu kaligi undhi. adanapu chlorin anuvu undatam valana kriyaaseela allilic metabolites nundi erpadina catayans yokka sthirathvam taggutundi, tadwara alcalation sambhaavyata taggutundi, mariyu vaastavaaniki toramifane elukala hepatocyteslo dna adduct erpadataanni pradarsinchadu. toramifine andaasayapu eluka namoonaalalo emuka nashtam nundi rakshistundi mariyu tamoxifen maadirigaane emuka punarviniyoga gurtulanu vaidyaparamgaa prabhaavitam chestundi. tamoxifen vanti microsomal cytochrome pii450 enjaimla dwara toramifane modati dasha jeevakriyaku lonavutundi, conny pradhanamgaa saip3eah4 isopharm dwara. toramifine daani rendu pradhana gvakriyalu enn-desmethyltoremiphine mariyu deminohydroxy-toramifine (aspemiphene) nuu enn-demethylation mariyu demination-hydroxylation dwara yerparustundi. enn-desmethyltoremiphine toremiphene maadirigaane saamarthyaanni kaligi undagaa, 4-hydroxytoremiphine toremiphene kante ertho ekkuva bandhinche anubandhaanni kaligi untundi. 4-hydroxytoremiphine 4-hydroxytamoxifen paatranu pooli untundi.
rendava taram benzotheophenes.
raloxifine rendava taram benzotheophene serm aushadhaalaku chendinadi. idhi estradiol nundi bhinnamaina saktivantamaina anty eestrogenik charya mariyu kanajaala-nirdishta prabhaavaalato err patla adhika anubandhaanni kaligi undhi. raloxifane anedi emuka mariyu hridayanaala vyavasthalo err agonist, conny rommu kanajaalam mariyu endometriumlo idhi err virodhigaa panichestundi. idhi pegulo glucuronide samyogam dwara vistrutamgaa jeevakriya cheyabadutundi mariyu daani kaaranamgaa kevalam 2 saatam takkuva jeeva labhyata kaligi undagaa, tamoxifen mariyu toramifane sumaruga 100% gaa untaayi.
triphenylethylene tamoxifen kante raloxifen yokka prayojanam garbhasayam meeda prabhavam taggutundi. anuvaina keelu samuuham, alaage anty eestrogenik phenyl 4-pyperidenoethoxy side chain, garbhasaya prabhavalanu tagginchadaaniki mukhyamainavi. daani vasyata kaaranamgaa side chain korku sambandhinchi orthogonal swabhaavaanni pondagaladu, tadwara raloxifence side chain yokka amine era yokka ligand-binding domainlo amaino assid asp-351kii tamoxiphanes kante 1 kii daggaragaa untundi.
serm-err complexes yokka bahya uparitalam yokka aakaram mariyu chaarj rendintinee maarchadaaniki raloxifane yokka hydrophobic side chain mariyu receptor yokka hydrophobic avasheshaala madhya sannihita sambandham yokka keelaka paatra raloxifane utpannaalato nirdhaarinchabadindi. raloxifine mariyu eah. ess. pii.-351 madhya paraspara dooraanni 2.7 nundi <ii. dii. 1> kii penchinappudu, idhi raloxifine-era complexes yokka eastrogen lanty charyanu penchutundi. raloxifin yokka piperidine ring cyclohexane dwara bharti cheyabadinappudu, ligand eestrogenik vyatiraeka lakshanaalanu kolpoyi puurti agonist avutundi. serm yokka anty eestrogenik side chain mariyu amaino assid aspi-351 madhya paraspara charya anedi af-2 nuu nissabdam cheyadamlo mukhyamaina modati dasha. idhi ligand-binding paaket nundi helix 12nii dhooramgaa maarchutundi, tadwara coactivatorlanu serm-err complexeku bandhinchakundaa nirodhistundi.
moodo taram.
moodava taram sammelanaalu garbhasaya uddeepana, merugaina shakti, vaedi flushlalo gananeeyamaina perugudala ledhaa eee saanukuula lakshanaala kalayikanu kooda pradarsinchavu.
modati dihydronapthalene serm, nafaxidine, rommu cancer chikitsaku clinical abhyardhi, conny teevramaina phototoxicitytho sahaa dushprabhaavaalanu kaligi undhi. nafaxidine moodu phenylsnu tamoxifen vanti coplaner amarikalo parimitam chestundi. conny hydrogenationtho, nafaxidine yokka dwandwa bandham taggipoyindi, mariyu rendu phenyls sis-aadhaaritamainavi. amine-baring side chain appudu akshasambandhamaina aakrutini sweekarinchi, ralofoxifane mariyu itara takkuva garbhasaya kanajaalam vanti core yokka samatalaaniki eee samuuhaanni artogonalga gurtinchavacchu.
nafaxidine yokka maarpulu lasphoxifineku daariteesaayi. emuka nashtam mariyu collustroll taggimpu nundi rakshanalo namodaina atyanta saktivantamaina sermlalo lasophoxiphane okati. lasophoxiphane yokka adbhutamaina noti shakti final yokka pegu glucuronidation taggadaaniki kaaranamani cheppabadindi. raloxifine maadirigaa kakunda, gut wall glucuronidationku nirodhakatanu anchanaa vese pharmacophore modal avasaranni lasophoxiphine santruptiparustundi. nirmaana avasaram anedi oka sthiramaina sthuulakaayam gala naan-planner topology, idhi fused cyclic sugandha vyavastha yokka samatalaaniki daggaragaa untundi. err mariyu lasophoxiphane madhya paraspara charyalu serm-err gurtimpu yokka saadhaarana lakshanaalaku anugunamgaa untaayi. lasophoxiphane yokka pedda anuvaina side chain pyrolydine head grouplo mugustundi mariyu protein uparitalam vaipu daani marganni daaram chestundi, akkada idhi neerugaa af-2 helix sthaanaaniki antaraayam kaligistundi. lasophoxiphine mariyu eah. ess. pii-351 madhya oka uppu vantena erpadutundi. eee praantamloo chaarj tatastheekarana anedi lasophoxiphine dwara kaliginche konni eestrogenik vyatiraeka prabhavalanu vivarinchavacchu.
indol vyavastha sermlalo pradhana vibhagamga panichesindi, mariyu oka amainnu benzyloxythyltho indolku jodinchinappudu, phalitamgaa vachhe sammelanaalu takkuva motaadulo puurti saamardhyamtho eluka emukanu vidichipetti, preclinical garbhasaya karyakalapalanu kaligi undavani choopabadindi. aaa sammelanaalalo bajedoxifine okati. core binding domainlo 2-phenyl-3-methyl indol mariyu side chain affector praantamloo hexamethylenamine ring untaayi. idhi glucuronidation dwara jeevakriya cheyabadutundi, sampoorna jeeva labhyata 6.2%, idhi raloxifin kante 3 retlu ekkuva. idhi emuka mariyu lipid jeevakriyapai agonistic prabhavalanu kaligi untundi, conny rommu mariyu garbhasaya endometriumpy kaadu. idhi baga thattukogaladu mariyu hott flush sanghatanalu, garbhasaya hypertrophy ledhaa rommu sunnitatvam peragadu.
aspemiphene anedi triphenylethylene mariyu toremiphene yokka telisina metabolite. idhi nirmanatmakamga tamoxifen mariyu toraemipheenlanu pooli untundi. aspemiphine loe tamoxifen gaa 2-(dimethylamino) ethoxy samuuham undadu. nirmaanam-kaaryaacharana sambandha adhyayanalu garbhasayamloni tamoxifen agonistic karyakalapala samuuhaanni tolaginchadam dwara gananeeyamgaa tagginchabadindani choopinchaayi, conny emuka mariyu hridayanaala vyavasthalo kaadu. preclinical mariyu clinical dayta aspemiphane etuvanti pedda dushprabhaavaalu lekunda baga thattukogaladani choopistundi. itara sermla kante aspemiphane kaligi unde prayojanaalu emitante, vaedi flushlupy daani tatastha prabhavam mariyu yonipai err-agonist prabhavam, yoni podigaa unde lakshanaalanu meruguparustundi.
binding modlu.
eee serms naalugu vilakshanhamaina err binding modlanu kaligi untaayi. aaa lakshanaalalo okati ligand mariyu ara yokka arg-394 mariyu gloo-353 madhya balamaina hydrogen bandhaalu, ivi "eah-ring paaket" nuu varusalo unchutaayi mariyu ligand err yokka binding paaketlo undataaniki sahaayapadataayi. idhi 17β-estradiol kuu bhinnamgaa untundi, idhi "dii-ring paaket" loe athani-524 thoo bandhinchabadina hydrogen. ligand-binding paaketku itara vilakshanhamaina bandhaalu saadhaaranamgaa bayaril heterocycletho koodi untaayi, idhi 17β-estradiol yokka eah-ring mariyu bii-ring kuu samanam, sambandhita binding saitku; 17β-estradiol yokka bii-ring kii saaruupyamaina bayaril nirmaanam nundi oka sthuulamaina side chain mariyu chivaraku sii-mariyu dii-ring samaanamaina mariyu saadhaaranamgaa sugandhabharitamaina rendava vaipu samuuham, ligand-binding paaket yokka migilina vaalyuumnu nimputundi.
rendu uparakaala madhya chinna thedaalu uparakam-selective err modulatorlanu abhivruddhi cheyadaaniki upayoginchabaddaayi, ayithe rendu graahakaala madhya adhika saaruupyata abhivruddhini chaalaa savaluga chestundi. ligand-binding domainlalo amaino aamlalu rendu sthaanaalalo bhinnamgaa untaayi, lyuu-384 mariyu erlo mett-421 mariyu erbitaalo mett-336 mariyu ail-373, conny avi oke vidhamaina hydrophobicity mariyu aakraminche parimaanaalanu kaligi untaayi. ayithe, amaino aamlam avasheshaala akaaraalu mariyu bhramana avarodham okela undavu, idhi era mariyu erbita madhya binding kuharam yokka α-mariyu β-mukhanni vaeru cheyadaaniki daariteestundi. idhi meat-336kii edurugaa krindiki samalekhanam cheyabadina ligand pratyaamnaayaala yokka era-preferential-binding kuu kaaranamavutundi, ayithe meat-336kii edurugaa paiki samalekhanam cheyabadina ligand pratyaamnaayaalu erbitatho bandhinche avakaasam ekkuvagaa untundi. maroka vyatyaasam erlo wall-392loe undhi, idhi erbitaalo mett-344thoo bharti cheyabadutundi. erbita yokka binding paaket valume konchem takkuvagaa untundi mariyu aakaram era nundi konchem bhinnamgaa untundi. aneka erbita-selective ligandlu ekkuvagaa samathattaina amarikanu kaligi untaayi, endukante erbita yokka binding kuharam era kante konchem irukainadi, ayithe, idhi swayamgaa niraadambaramaina empikaku daariteestundi. balamaina empikanu saadhinchadaaniki, ligand itara uparaka grahakam vaipu balamaina vikarshana saktini srushtinchadaaniki era mariyu erbita madhya okati ledhaa anthakante ekkuva amaino aamlam vyatyaasaalaku chaalaa daggaragaa pratyaamnaayaalanu unchaali. adanamgaa, ligand yokka nirmaanam drudhamgaa undaali. vikarshana paraspara charyalu ligand yokka conformational maarpuku daariteeyavachchu, anduvalla, pratyaamnaaya binding modlanu srushtinchavachu.
modati taram triphenylathylenes.
tamoxifen kaaleya cytochrome p450 dwara 4-hydroxytamoxifengsifeng maarchabadutundi mariyu idhi erbita kante era uparakam yokka marinta empika chesina virodhi. 4-hydroxytamoxifen 17β-estradiolnu gurtinche adhe binding paaket lopala ers thoo bandhistundi. 4-hydroxytamoxifen yokka grahaka gurtimpu 4-hydroxytamoxifen, phenolic ring mariyu sthuulamaina side chain anae rendu nirmaana lakshanaala dwara niyantrinchabadutundani telustondi. phenolic ring anedi err yokka arg-394, gloo-344 yokka side groupulaku mariyu nirmanatmakamga samrakshinchabadina neetiki hydrogen bandhaalanu yerparustundi. binding kuharam nundi poduchukunna sthuulamaina side chain, ligand-binding paaket nundi helix 12 nuu sthaanabhramsham chesi coactivator binding paaket yokka bhaganni cover chestundi. err-4-hydroxytamoxifen complexes nirmaanam corpressors proteinlanu niyamistundi. idhi dna samslaeshanha taggadaaniki mariyu eastrogen charyanu nirodhinchadaaniki daariteestundi. chlomiphane mariyu torimephane tamoxifen maadirigaane bandha sambandhaalanu utpatti chestaayi. anduvalla, eee rendu mandulu erbita kante era uparakam yokka marinta empika chesina pratyarthulu.
rendava taram benzotheophenes.
4-hydroxytamoxifen maadirigaane raloxifine, arg-394 mariyu gloo-353 thoo hydrogen bandhaala dwara daani phenolic "oka ring" yokka hydroxyl samuuhamtoe eretho bandhistundi. eee bandhaalatho paatu, raloxifine thana 524 yokka side group dwara err kuu rendava hydrogen bandhaanni yerparustundi endukante "dii ring" loe rendava hydroxyl samuuham untundi. eee hydrogen bandham 17β-estradiol mariyu athani-524 madhya kakunda untundi, endukante athani-524 yokka imidazole ring raloxifine mariyu 17β-estradiol loe oxygen sthaanam yokka vyatyaasaanni edurkovadaniki tippabadutundi. 4-hydroxytamoxifen maadirigaane, raloxifin yokka sthuulamaina side chain helix 12nii sthaanabhramsham chestundi.
moodo taram.
daadaapu planner topology (tetrahydronapthalline carbosycle), arg-394 mariyu gloo-353 thoo hydrogen bandham mariyu ligand-binding paaket yokka sii-ring mariyu dii-ring vaalyuumnu nimpe lasophoxiphane yokka phenyl side chains vanti serm-era madhya paraspara charyaku era thoo lasophoxiphane paraspara charya vilakshanamainadi. lasophoxiphane helix 12nii mallistundi mariyu lxxl uddesyaalato coactivator proteinla bandhaanni nirodhistundi. saadhaaranamgaa lyuu-540 yokka side group dwara nimpabadina sthalaanni aakraminchi, helix 11 (athani-524, lyuu-525) yokka avasheshaala nirmaanaanni modulate cheyadam dwara lasophoxiphane dheenini saadhistundi. inca, eethail pyrolydine samuuham dwara helix 12 sthaanaaniki kooda lasophoxiphane neerugaa jokyam chesukuntundi. era mariyu erba rendintikee adhika mariyu saaruupya bandham dwara 17bita-estradiolnu bajedoxifen poteegaa nirodhistundani inn vitro adhyayanalu suuchistunnaayi. bazedoxifence pradhana binding domainlo 2-phenyl-3-methylindol mariyu side chain prabhaavita praantamloo hexamethylenamine ring untaayi.
aspemiphene anedi toremiphene yokka aakseekarana deaminated metabolite, idhi toremiphene mariyu tamoxifen vanti vatiki samaanamaina bandham kaligi untundi. moodu gvakriyalu 4-hydroxy aspemiphene, 4-hydroxy aspemiphene mariyu 4-hydroxy-, side chain carboxylic aamlam aspemiphene yokka era mariyu erbitaaku pootii bandham kaneesam maatru sammelanam antha ekkuvagaa untundi.
charitra.
kotta garbhanirodhaka mandulanu abhivruddhi chese prayatnaala phalitamgaa serms aavishkarana jarigindi. chlomiphane mariyu tamoxifen elukalalo garbham dharinchadaanni nirodhinchaayi, conny maanavulalo dheeniki viruddhamgaa chesaayi. chlomiphane phaladeekaranaaniki lobadi unna mahilallo andotsargamunu vijayavantamgaa prerepinchindi mariyu fibravari 1,1967naa, garbham dharinchadaaniki prayatnistunna mahilallo andotsargamunu panicheyakapovadam chikitsa kosam idhi USloe aamodinchabadindi. vishasambandha samasyalu chlomiphane yokka deerghakaalika vadakanni mariyu rommu cancer chikitsa mariyu nivaarana vanti itara sambhaavya anuvartanaala kosam marinta aushadha abhivruddhini nirodhinchaayi.
1977 decemberlo tamoxifen aamodinchabadataaniki maroe padeella mundu, garbhanirodhakamgaa kaadu, rommu cancerku chikitsa cheyadaaniki mariyu nivaarinchadaaniki harmonela chikitsagaa. rommu kanajaalamlo vyatiraeka prabhaavaala kaaranamgaa eastrogen vyatiraekatagaa bhaavinche tamoxifen mariyu raloxifen anae serms, andaasayapu elukalalo emuka nashtam nivaarinchadamlo eestrogenik prabhavalanu chuupaayani 1987loe kanugonabadindi, saadhaaranamgaa eastrogen grahakaalu mariyu anhu graahakaala paniteerupai mana avagaahanapai goppa prabhavanni choopindi. kanajaalaanni batti eastrogen agonist, pakshika agonist ledhaa virodhi karyakalapala kalayikanu kaligi unna eee sammelanaalanu vivarinchadaaniki serm anae padaanni pravesapettaaru. toramifane tamoxifencu anukuulamgaa unnatlu choopabadindi, mariyu 1996loe rutukramam aagipoyina mahilallo rommu cancer chikitsalo upayoginchadaaniki idhi aamodinchabadindi.
prayogasaalalo tamoxifento poliste paelavamaina paniteeru kaaranamgaa raloxifane modata rommu cancer aushadhamgaa viphalamaindi, ayithe emukapai raloxifane yokka eestrogenik prabhavalu 1997loe daani punahshodhana mariyu aamodaaniki daariteesaayi. bolu emukala vyaadhi nivaarana mariyu chikitsa kosam idhi aamodinchabadindi mariyu bolu emukala vyaadhi mariyu rommu cancer rendintinee nivaarinchadaaniki vaidyaparamgaa andubaatulo unna modati serm. rutuvirati kaaranamgaa, vulver mariyu yoni ksheenata yokka lakshanam ayina mitamaina nundi teevramaina dysperania chikitsa kosam aspemiphane fibravari 26,2013naa aamodinchabadindi. rutuvirati thoo mudipadi unna vasomotor lakshanaala chikitsa kosam samyugmita eestrojenlu mariyu serm bajedoxifine thoo kalipi chikitsa october 3,2013naa aamodinchabadindi. rutukramam aagipoyina bolu emukala vyaadhi nivaaranaloo kooda bajedoxifane upayoginchabadutundi. emukala samarthatha mariyu raloxifin kante merugaina jeeva labhyatatho kuudina saktivantamaina serm kosam anveshana lasophoxiphine aavishkaranaku daariteesindi. 2009loe lasophoxiphane aamodinchabadinappatiki, aamodam pondina taruvaata moodu samvatsaraalu idhi vikrayinchabadaledu, kabatti dheeniki marketing adhikaram gaduvu mugisindi. airopalo, rutukramam aagipoyina mahilallo bolu emukala vyaadhi chikitsa kosam bajedoxifane suuchimchabadutumdi, ayithe bhaaratadesamlo ormeloxifane panicheyani garbhasaya raktasraavam mariyu janana niyantrana kosam upayoginchabadutundi.

