Lecirelin acetate hmoovyog ib qho kev sib xyaw ua ke octapeptide analogue ntawm somatostatin, koom nrog hauv chav kawm ntawm somatostatin receptor ligands (SRLs). Nws cov qauv tshuaj yog C59H84N16O12, qhov hnyav molecular yog 1096.34, thiab CAS rau npe yog 108736-35-2. Cov tshuaj tau tsim los ntawm Ipsen Pharma Biotech Sas hauv Fabkis, thiab nws lub npe lag luam yog Somatuline Depot. Nws tau pom zoo thawj zaug rau kev ua lag luam hauv European Union thaum Lub Ob Hlis 2005, tau pom zoo los ntawm US FDA thaum Lub Yim Hli 2007, thiab tau pom zoo rau kev kho mob acromegaly hauv Suav teb thaum Lub Kaum Ob Hlis 2007.
Peb cov khoom Form
Lecirelin COA
Lecirelin acetate hmoovtam sim no yog thawj qhov kev tsim ua tiav kev txhawb nqa - tso tawm cov tshuaj somatostatin, thiab yog ib qho tshiab ntev - ua yeeb yam somatostatin (SM) octapeptide analogue. Nws yog peptide inhibitor rau ntau yam endocrine, neuroendocrine, exocrine, thiab paracrine zog. Cov kev tshawb fawb tau pom tias nws feem ntau tuaj yeem siv nws cov teebmeem los ntawm kev khi rau somatostatin receptors (SMRs), nrog kev sib raug zoo zoo rau peripheral (pituitary thiab pancreatic) SMRs thiab tsis muaj zog affinity rau central receptors.
1. Prostate cancer
Nws yog maj mam tshwm sim hauv kev kho mob qog noj ntshav prostate, thiab nws cov peev txheej kho tau raug tshawb nrhiav thiab lees paub tas li.
Mob pob txha metastasis:
Cov neeg mob qog noj ntshav prostate feem ntau ntsib cov pob txha metastasis, thiab qhov mob tshwm sim los ntawm cov pob txha metastasis cuam tshuam rau tus neeg mob lub neej zoo thiab muaj peev xwm ua haujlwm txhua hnub. Kev sib xyaw ntawm bisphosphonates muab kev kho mob zoo rau kev kho pob txha metastasis mob. Bisphosphonates tuaj yeem cuam tshuam cov kev ua ntawm osteoclasts, txo cov pob txha resorption, txhim khu pob txha muaj zog, thiab tiv thaiv qhov tshwm sim ntawm cov pob txha ntsig txog cov xwm txheej (SREs) xws li pob txha. Dhau li ntawm muaj kev tiv thaiv ncaj qha -cov teebmeem qog, acetic acid lanrelitid kuj tseem tuaj yeem txhim kho microenvironment ntawm cov pob txha metastasis qhov chaw los ntawm kev tswj cov kev qhia ntawm cov pob txha metabolism ntsig txog yam. Kev sib xyaw ua ke ntawm ob tuaj yeem ua rau muaj kev sib koom ua ke, ua kom muaj txiaj ntsig zoo ntawm cov pob txha mob, txo qhov zaus ntawm cov pob txha ntsig txog cov xwm txheej, thiab txo qhov mob ntawm cov neeg mob.
2. mob cancer mis
Kev tshawb nrhiav hauv kev kho mob qog noj ntshav mis kuj tau ua qee yam kev vam meej, muab ntau txoj kev kho mob rau cov neeg mob qog noj ntshav.
Kev tswj cov pob txha metastasis:
Cov neeg mob qog nqaij hlav hauv lub mis tseem ua rau cov pob txha metastasis, uas tuaj yeem ua rau muaj teeb meem loj xws li mob pob txha thiab pob txha, thiab cuam tshuam rau lub neej zoo ntawm cov neeg mob. Kev sib xyaw nrog cov tshuaj tiv thaiv pob txha resorption yog ib lub tswv yim zoo los tswj cov pob txha metastasis ntawm mob qog noj ntshav mis. Cov tshuaj tiv thaiv pob txha resorption xws li zoledronic acid tuaj yeem cuam tshuam cov haujlwm ntawm osteoclasts, txo cov pob txha resorption, thiab txhim kho pob txha muaj zog. Ntxiv nrog rau nws cov tshuaj tiv thaiv -cov nyhuv qog, nws kuj tseem tuaj yeem tswj cov pob txha metabolism, txhawb kev tsim cov pob txha, sib koom ua ke nrog cov tshuaj tiv thaiv pob txha resorption, zoo dua txo cov pob txha mob, tiv thaiv pob txha, thiab txhim kho cov neeg mob tus kheej - kev tu lub peev xwm.
Muaj peev xwm ntawm Kev Kho Mob Ua Ke: Synergistic Enhancement Strategy
Kev sib xyaw ua ke nrog lwm cov tshuaj tuaj yeem txhim kho cov txiaj ntsig ntawm kev kho mob, nthuav qhia kev kho mob, thiab ua rau muaj kev cuam tshuam tshiab rau kev kho mob ntawm ntau yam kab mob.
Ua ke nrog cov tshuaj tsom
Piv txwv li, kev sib xyaw ua ke ntawm lanrelitide acetate thiab everolimus tau ua tiav cov txiaj ntsig zoo hauv kev kho mob plab hnyuv siab rau pancreatic neuroendocrine hlav (GEP NETs). Everolimus yog cov tshuaj tiv thaiv kab mob qog noj ntshav ntawm lub hom phiaj protein ntawm rapamycin (mTOR), uas tuaj yeem cuam tshuam kev loj hlob thiab kev loj hlob ntawm cov qog hlwb. Los ntawm inhibiting lub secretion ntawm kev loj hlob yam xws li kev loj hlob hormone thiab insulin-zoo li kev loj hlob factor-1 (IGF-1), qhov chaw loj hlob ntawm cov qog hlwb raug tswj. Kev sib xyaw ua ke ntawm ob tuaj yeem ua rau muaj kev sib koom ua ke, inhibiting kev loj hlob thiab metastasis ntawm cov qog hlwb los ntawm ntau yam. Cov txiaj ntsig ntawm ELECT txoj kev tshawb fawb qhia tau hais tias qhov kev sib xyaw ua ke no tuaj yeem ua rau muaj kev vam meej tsis muaj sia nyob (PFS) ntawm cov neeg mob mus txog 16.5 lub hlis, muab kev kho mob zoo dua rau cov neeg mob GEP NETs siab.
Ua ke nrog chemotherapy
Kev siv tshuaj khomob yog ib txoj kev kho mob uas feem ntau siv rau hauv kev kho mob uas tsis yog -mob qog nqaij hlav hauv lub ntsws, tab sis cov tshuaj khomob feem ntau ua rau muaj kev cuam tshuam tsis zoo, xws li xeev siab, ntuav, thiab mucosal o, uas cuam tshuam rau tus neeg mob lub neej thiab kev kho mob. Kev siv ua ke nrog cov tshuaj chemotherapy tuaj yeem muaj qhov tshwj xeeb zoo. Nws tuaj yeem tiv thaiv lub plab hnyuv mucosa, txo qhov kev puas tsuaj ntawm cov tshuaj tua kab mob rau lub plab hnyuv mucosa, yog li txo qhov tshwm sim thiab qhov hnyav ntawm cov tshuaj tua kab mob - ua rau xeev siab, ntuav, thiab mucosal o. Qhov no ua rau cov neeg mob tuaj yeem zam tau cov tshuaj khomob zoo dua, ua kom muaj kev vam meej ntawm kev siv tshuaj khomob thiab txhim kho kev kho mob.
Ua ke nrog immunotherapy
Immunotherapy yog ib qho tseem ceeb hauv kev kho mob qog noj ntshav hauv xyoo tas los no. Cov tshuaj tiv thaiv kab mob tiv thaiv kab mob xws li PD-1/PD-L1 inhibitors tuaj yeem ua rau lub cev tiv thaiv kab mob thiab txhim kho cov tshuaj tua kab mob ntawm cov qog hlwb. Kev sib xyaw nrog cov tshuaj tiv thaiv kab mob tuaj yeem txhim kho qhov ua tau zoo ntawm PD-1 / PD-L1 inhibitors los ntawm kev tswj hwm lub cev tiv thaiv kab mob hauv cov qog microenvironment. Muaj ntau yam kev tiv thaiv kab mob tiv thaiv kab mob thiab lwm yam hauv cov qog microenvironment uas inhibit qhov kev ua haujlwm thiab kev ua haujlwm ntawm lub cev tiv thaiv kab mob, ua rau cov qog hlwb kom tsis txhob muaj kev tiv thaiv kab mob. Nws yog ib qho ua tau los txhim kho lub cev tiv thaiv kab mob ntawm cov qog microenvironment, txhawb kev tiv thaiv kab mob hauv lub cev thiab tua cov qog hlwb, thiab txhim kho kev ua haujlwm ntawm kev tiv thaiv kab mob los ntawm kev tswj cov kev qhia ntawm cov kab mob immunosuppressive thiab yam tseem ceeb.
Kev tshawb nrhiav thiab kev txhim kho thiab kev tshawb pom keeb kwm yav dhau los
Kev tshawb fawb thiab kev txhim kho keeb kwm yav dhau: Kev tsim cov txheej txheem kev tsim tawm raws li GnRH
Nws yog ib qho hluavtaws gonadotropin- tso cov tshuaj hormone (GnRH) analog. GnRH yog peptide hormone secreted los ntawm hypothalamus, uas tswj kev loj hlob ntawm gonadal thiab kev loj hlob ntawm lub voj voog los ntawm kev txhawb kev tso tawm ntawm follicle stimulating hormone (FSH) thiab luteinizing hormone (LH) los ntawm cov qog pituitary anterior. Hauv thaj teb ntawm tsiaj yug me nyuam, kev loj hlob ntawm GnRH analogs lub hom phiaj los daws cov teeb meem hauv qab no:
Ovarian dysfunction:
Xws li bovine zes qe menyuam follicular cysts, ua rau ovulation teeb meem thiab txo cov qe menyuam.
Synchronization ntawm kev yug me nyuam:
Txhim kho qhov ua tau zoo ntawm cov khoom siv dag zog thiab txhim kho cov tsiaj txhu ntau lawm.
Kev txwv ntawm kev kho tshuaj hormone:
Ntuj GnRH muaj ib nrab luv luv - lub neej thiab yuav tsum tau txhaj tshuaj nquag, thaum cov khoom siv hluavtaws tuaj yeem siv sijhawm ntev ntawm kev ua haujlwm los ntawm kev hloov kho cov qauv.
Discovery Process: Optimization ntawm Natural GnRH rau Lecirelin
Kev txheeb xyuas ntawm Natural GnRH:
Xyoo 1971, Schally thiab Guillemin pab pawg thawj zaug cais GnRH los ntawm hypothalamus ntawm npua thiab txiav txim siab nws cov qauv decapeptide (pGlu Nws Trp Ser Tyr Gly Leu Arg Pro Gly NH2). Qhov kev tshawb pom no tau tsim lub hauv paus rau kev kawm ntawm cov khoom siv hluavtaws.
Kev hloov kho cov qauv thiab kev ua kom zoo dua qub:
Los ntawm kev hloov lossis hloov cov amino acid residues ntawm ntuj GnRH, cov kws tshawb fawb tau tsim ntau yam analogues tsom rau:
Nws cov amino acid sequence yog H-Pyr-Nws-Trp-Ser-Tyr-D-Gly (tBu) - Leu-Arg-Pro-NHEt, qhov twg:
D-Gly (tBu):
Kev hloov kho tertiary butyl ntawm D-hom glycine txhim kho nws cov kev tiv thaiv rau enzymatic hydrolysis.
Pro NHEt:
Kev hloov kho ethylation ntawm proline prolongs lub sijhawm ua haujlwm.
Kev kuaj xyuas tsiaj txhu:
Kev tshawb fawb tau pom tias n tuaj yeem ua rau muaj kev sib kis ntau zaus ntawm bovine preovulatory follicles, txhawb nqa follicle maturation thiab ovulation. Piv txwv li, nyob rau hauv hybrid nyuj, kev txhaj tshuaj nyob rau hnub 7th tom qab kev tsim cov tshuaj tua kab mob tuaj yeem ua rau muaj kev xeeb tub thiab tswj cov ntshav progesterone.
R & D tseem ceeb: los ntawm chav kuaj mus rau kev kho mob
Kev tshawb fawb thiab kev loj hlob ntawm hluavtaws GnRH analogs (xws li Buserelin thiab Triptorelin) tau txheeb xyuas cov txiaj ntsig ntawm kev hloov kho cov qauv ntawm kev ua ub no, thiab kev sib xyaw ua ntej thiab kev tshuaj ntsuam xyuas hauv vitro.
Pom zoo rau kev kho mob ntawm bovine zes qe menyuam follicular cysts, nws tau dhau los ua ib qho tseem ceeb ntawm kev tswj cov menyuam hauv kev yug tsiaj.
Kev tshawb fawb txuas mus rau lwm yam tsiaj xws li nees thiab npua los tshawb txog lawv cov ntawv thov hauv kev ua kom ovulation thiab synchronizing estrus.
Txawm hais tias feem ntau siv rau hauv cov tshuaj kho tsiaj, nws txoj kev txhim kho cov qauv tsim tau txhawb kev txhim kho ntawm tib neeg GnRH analogs (xws li Degarelix, siv rau kev kho mob qog noj ntshav prostate).
Txoj kev npaj:
Tom qab tshem tawm cov pab pawg tiv thaiv Fmoc ntawm Rink amide resin, thawj cov amino acid Fmoc Thr (tBu) yog loaded rau hauv cov resin los ntawm cov pa coupling. Ntxuav cov resin, tshem tawm cov pab pawg tiv thaiv Fmoc, thiab qhia cov amino acid thib ob Fmoc Cys (Acm) los pib qhov kev sib txuas thib ob. Ua ntej, qhib cov amino acids tiv thaiv los ntawm Fmoc siv TBTU / HOBt, thiab tom qab ntawd ua kev sib txuas siv diisopropylethylamine lossis methyl pyridine ua cov organic hauv paus (qhia los ntawm kev sim indene ketone los txiav txim seb qhov sib txuas puas tiav). Ntxuav cov resin thiab tshem tawm cov pab pawg Fmoc ntawm -amine siv cov tshuaj DMF uas muaj 20% piperidine los ntawm ntim (p). Raws li peptide ib ntus, rov ua cov kauj ruam saum toj no nrog cov amino acids sib txawv txhua zaus [tag nrho cov amino acids siv tau tiv thaiv nrog Fmoc-N; Tyr(tBu), Lys(Boc), Thr(tBu), Cys(Trt). Ntxuav cov resin nrog DMF thiab tom qab ntawd nqus nws nrog DCM. Ntxuav nrog cov kuab tshuaj uas muaj 95% (p) TFA, 2.5% (p) TIS, thiab 2.5% (p) EDT kom tshem tawm cov kua qaub tiv thaiv cov pab pawg thiab cais cov peptide ntawm cov resin. Ntxiv ether rau precipitate cov khoom, lim, thiab lub tshuab nqus tsev qhuav. Kev lim dej siv C18 thim rov qab theem siab -koom ua kua chromatography. Ntxiv ib qho sib npaug ntawm cov tshuaj iodoacetic acid uas muaj zog nplawm ntawm chav tsev kub (neutralize tshaj iodine nrog me me ntawm ascorbic acid). Cov kev daws tau raug ntxuav kom huv siv C18 thim rov qab theem siab -kev ua haujlwm ua kua chromatography kem kom tau txais lanrui peptide. Hloov cov ions sib npaug hauv feem nrog acetate, sau cov feem, sublime, qhuav, thiab tau txais lanaritide acetate.
Cim npe nrov: Tuam Tshoj lecirelin acetate manufacturers, lwm tus neeg
