Shaanxi BLOOM Tech Co., Ltd. yog ib qho ntawm cov tuam ntxhab thiab cov muag khoom ntawm icatibant hauv Suav teb. Txais tos rau kev lag luam wholesale bulk zoo icatibant muag ntawm no los ntawm peb lub hoobkas. Kev pabcuam zoo thiab tus nqi tsim nyog muaj.
Icatibantyog ib qho khoom siv hluavtaws peptide tshuaj nrog cov qauv molecular ntawm C59H89N19O13S thiab qhov hnyav molecular raug rau 1304.54. Cov tshuaj yog tsim los ntawm 18 amino acids, suav nrog ntau yam tsis muaj cov amino acids xws li D-arginine (D-}Arg), thiazole alanine (Thi), D-tertiary leucine (D-Tic), thiab ornithine (Oic). Nws qhov tshwj xeeb amino acid kev npaj ua rau nws muaj kev ua haujlwm lom neeg tshwj xeeb, xws li qhia txog kev cuam tshuam steric los ntawm kev hloov kho cov amino acids los txhim kho kev khi tshwj xeeb nrog lub hom phiaj receptors.
Cov khoom Form
Cov khoom siv COA
 |
||
| Certificate of Analysis | ||
| Compound npe | Icatibant | |
| Qib | Pharmaceutical qib | |
| CAS Nr. | 130308-48-4 | |
| Ntau | 78g | |
| Ntim txheem | PE hnab + Al foil hnab | |
| Chaw tsim tshuaj paus | Shaanxi BLOOM TECH Co., Ltd | |
| Ntau No. | 202601090056 | |
| MFG | Peb 9, 2026 | |
| EXP | Peb 8, 2029 | |
| Qauv |
|
|
| Yam khoom | Enterprise txheem | Kev txheeb xyuas qhov tshwm sim |
| Qhov tshwm sim | Dawb los yog yuav luag dawb hmoov | Ua raws |
| Cov ntsiab lus dej | Tsawg dua lossis sib npaug li 5.0% | 0.32% |
| Poob rau ziab | Tsawg dua lossis sib npaug li 1.0% | 0.17% |
| Hnyav Hlau | Pb Tsawg dua lossis sib npaug li 0.5ppm | N.D. |
| Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Hg Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Cd Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Purity (HPLC) | Ntau dua lossis sib npaug li 99.7% | 99.8% |
| Ib leeg impurity | <0.8% | 0.54% |
| Tag nrho microbial suav | Tsawg dua lossis sib npaug li 750cfu / g | 90 |
| E. Coli | Tsawg dua lossis sib npaug li 2MPN / g | N.D. |
| Salmonella | N.D. | N.D. |
| Ethanol (los ntawm GC) | Tsawg dua lossis sib npaug li 5000ppm | 500ppm ua |
| Cia | Khaws rau hauv qhov chaw kaw, tsaus, thiab qhuav hauv qab 2-8 degree | |
|
|
||
|
|
||
| C.F: | C59H89N19O13S |
| E.M: | 1304 |
| M.W: | 1305 |
| m/z: | 1304 (100.0%), 1305 (63.8%), 1306 (20.0%), 1305 (6.6%), 1306 (4.5%), 1306 (4.5%), 1307 (4.1%), 1307 (2.9%), 1306 (2.7%), 1307 (1.7%), 1307 (1.3%), 1305 (1.0%) |
| E.A: | C, 54.32; H, 6.88; N, 20.40; O, 15.94; S, 2.46 |
Nws yog ib qho hluavtaws peptide uas muaj 10 amino acids (molecular mis: C ₅ H ₈ N ₁ O ₁ III S, molecular yuag: 1304.5), uas muaj 5 non natural amino acids (xws li D-Tic, Hyp, Thi, thiab lwm yam) nyob rau hauv nws cov qauv kev hloov pauv, thiab cov kev hloov pauv tshwj xeeb. Nws cov amino acid sequence yog Arg-Pro-Pro-Hyp-Gly-Ti-Ser-D-Tic-Oic-Arg, qhov twg:
D-Tic (D-2,3-diaminopropionic acid) thiab Oic (octahydroindole-2-carboxylic acid) yog cov amino acids uas tsis yog cov amino acids uas ua kom muaj peev xwm ua kom lub cev muaj peev xwm los ntawm steric hindrance thiab kev faib tawm.
Hyp (hydroxyproline) thiab Thi (thiazole alanine) txhim kho lawv txoj kev sib raug zoo rau receptors los ntawm hydrogen bonding thiab hydrophobic kev sib cuam tshuam.
Arg (arginine) residues ua raws li C-terminal qauv ntawm bradykinin thiab tsim tus choj ntsev nrog lub hnab ntim kua qaub ntawm B ₂ receptor.
Cov qauv tertiary: Nws folds rau hauv ib qho tshwj xeeb peb - qhov sib txawv ntawm qhov sib txawv ntawm hydrophobic kev sib cuam tshuam ntawm cov amino acid sab chains, ionic thiab hydrogen bonds, ua rau nws zoo heev rau qhov chaw khi ntawm B ₂ receptor. Nws affinity (Ki{2}} nM) zoo ib yam li bradykinin (Ki=0.3} nM), thiab nws tuaj yeem tiv thaiv kev degradation los ntawm bradykinin lyase. Nws txoj kev ua tau zoo yog 2-3 npaug siab dua li yav dhau los antagonists (xws li Hoe 140).
Icatibantyog ib qho hluavtaws xaiv bradykinin B2 receptor antagonist thiab peptide -raws li tus neeg saib xyuas kho mob. Nws yog feem ntau qhia rau qhov mob hnyav ntawm hereditary angioedema (HAE), thiab tseem ua haujlwm raws li cov tshuaj kho mob tshwj xeeb rau kev tswj hwm bradykinin- cov tshuaj tiv thaiv kab mob sib kis. Nws cov txheej txheem ntawm kev txiav txim yog nyob rau hauv qhov tseeb blockade ntawm bradykinin signaling txoj kev, uas fundamentally inhibits ib tug series ntawm pathological kev puas tsuaj los ntawm HAE tawm tsam.
Lub hauv paus pathogenesis ntawm hereditary angioedema tshwm sim los ntawm kev ua haujlwm tsis txaus lossis tsis txaus ntawm C1 esterase inhibitor hauv cov neeg mob. Raws li kev tswj hwm tseem ceeb ntawm kallikrein -bradykinin txoj hauv kev hauv tib neeg lub cev, kev ua haujlwm txawv txav ntawm cov inhibitor no ua rau muaj kev ua kom ntau dhau ntawm cov ntshav kallikrein. Lub overactivated kallikrein tsis tu ncua catalyzes qhov cleavage ntawm siab -molecular- hnyav kininogen los tsim kom muaj ntau ntawm active bradykinin, yog li ua rau muaj ntau yam kev kho mob tshwm sim.
Raws li ib tug muaj zog inflammatory thiab vasoactive peptide, bradykinin exerts physiological thiab pathological teebmeem tsuas yog los ntawm kev khi rau thiab activating bradykinin B2 receptors ntawm lub cell membrane. Kev faib tawm thoob plaws hauv cov hlab ntsha endothelial, cov hlab ntsha hauv cov leeg nqaij, cov kab mob hauv plab hnyuv thiab cov nqaij mos ntawm daim tawv nqaij, B2 receptors ua lub hom phiaj tseem ceeb kho mob edema, mob thiab mob. Raws li ib txwm muaj lub cev nqaij daim tawv, kev ua kom nquag plias ntawm B2 receptors los ntawm bradykinin koom nrog cov txheej txheem physiological xws li kev tswj hwm vascular thiab kev tswj hwm hauv zos microcirculation. Thaum lub sij hawm mob HAE tawm tsam, txawm li cas los xij, ntau dhau ntawm bradykinin tsis tu ncua thiab overactivates B2 receptors thiab pib cascaded pathological tshwm sim.
Ntawm ib sab tes, B2 receptor activation nthuav dav qhov sib txawv ntawm vascular endothelial hlwb thiab ua kom cov capillary permeability nce. Ib tug loj ntim ntawm intravascular kua extravasates mus rau hauv lub interstitial qhov chaw hauv qab ntawm daim tawv nqaij thiab mucous daim nyias nyias, ua rau lub zos edema uas feem ntau tshwm sim nyob rau hauv lub ntsej muag, extremities, pharynx thiab gastrointestinal ib ntsuj av. Pharyngeal edema tuaj yeem ua rau muaj kev cuam tshuam ntawm txoj hlab pa thiab tseem yuav ua rau lub neej - hem. Ntawm qhov tod tes, kev txhawb nqa kev ua kom muaj zog txhawb nqa kev tso tawm me me ntawm cov neeg kho mob hauv zos, ua rau cov ntaub so ntswg distending mob thiab kub hnyiab, nrog rau cov leeg nqaij du. Cov neeg mob plab hnyuv edema tuaj yeem tshwm sim nrog mob plab, xeev siab, ntuav thiab lwm yam tsis xis nyob.
Raws li kev sib tw B2 receptor antagonist, cov khoom lag luam sib koom ua ke ntawm cov qauv zoo nrog bradykinin. Nws tuaj yeem khi tshwj xeeb rau bradykinin B2 receptors ntawm lub cell membrane nrog kev sib raug zoo siab dua li endogenous bradykinin. Raws li kev khi, cov tshuaj nyob hauv qhov chaw receptor binding yam tsis tau ua kom qis qis qis qis qis, yog li cuam tshuam qhov kev khi thiab ua kom muaj zog ntawm cov endogenous bradykinin rau receptors thiab txiav tawm bradykinin - kho cov kab mob sib kis ntawm qhov chaw. Cov khoom lag luam ua tshwj xeeb ntawm B2 receptors thiab qhia tias tsis muaj kev cuam tshuam kev sib raug zoo rau bradykinin B1 receptors.
Txij li thaum B1 receptors feem ntau yog ntxias kom nthuav tawm tom qab mob inflammatory stimulation thiab tsis koom nrog qhov kev loj hlob ntawm HAE kev tawm tsam, cov tshuaj muaj lub hom phiaj zoo tshaj plaws thiab txo qis - cov teebmeem.
Tom qab kev tswj hwm, cov khoom lag luam thim rov qab sai sai bradykinin -induced vascular hyperpermeability, nres cov kua dej txuas ntxiv hauv cov ntaub so ntswg interstitium thiab ntes edema zuj zus, thaum txo cov leeg nqaij leeg thiab mob hauv zos.
Cov kev tshawb fawb soj ntsuam tau pom tias cov tshuaj tuaj yeem thaiv txoj hauv kev tsis zoo ntawm kev taw qhia tsis pub dhau kaum ob feeb tom qab siv tshuaj, maj mam daws cov teeb meem edema thiab sai sai txo cov tsos mob ntawm kev tawm tsam hnyav. Tsis tas li ntawd, cov khoom lag luam tsis cuam tshuam rau cov haujlwm tseem ceeb ntawm C1 esterase inhibitor lossis inhibit kev ua haujlwm ntawm kallikrein. Nws tsuas yog lub hom phiaj thiab thaiv txoj hauv kev hauv qab ntawm txoj kev pathological yam tsis cuam tshuam nrog cov ntshav coagulation ib txwm, fibrinolysis thiab kev tswj hwm microcirculation hauv lub cev. Nrog rau cov txheej txheem meej thiab muaj kev nyab xeeb ntawm kev nqis tes ua lub hom phiaj tseem ceeb ntawm cov kab mob sib txuas ntawm HAE raug mob hnyav, cov khoom tam sim no yog ib qho ntawm cov tshuaj kho mob tseem ceeb rau kev kho mob ntawm cov mob HAE mob.
Pharmacokinetics
Kev txhaj tshuaj subcutaneous yog txoj kev kho mob ib txwm sivicibant. Txoj hauv kev no sib phim cov khoom siv lub cev ntawm cov tshuaj, xa cov tshuaj pharmacokinetic ruaj khov nrog kev sib txuam qis - tus kheej hloov pauv, uas ua tau raws li qhov xav tau ntawm kev kho mob rau kev mob HAE hauv cov neeg laus.
Cov khoom yog absorbed sai heev nrog bioavailability siab heev tom qab txhaj tshuaj subcutaneous. Tom qab ib koob tshuaj ib zaug ntawm 30 mg, nws cov bioavailability tau nce mus txog 97% nrog ze li tsis muaj qhov nqus tau. Qhov siab tshaj plaws plasma concentration yog ua tiav kwv yees li 30 feeb tom qab- kev tswj hwm, ua kom muaj txiaj ntsig sai thiab ua kom txaus siab rau cov kev xav tau rau kev kho mob xwm txheej ceev ntawm kev tawm tsam hnyav.
Cov tshuaj muaj ib tug nruab nrab tis ntim nyob rau hauv vivo, nrog ib tug txhais tau tias khov kho - xeev ntim ntawm 29.0 ± 8.7 L. Nws muaj peev xwm txaus nkag mus rau hauv edematous lesions xws li daim tawv nqaij thiab mucous daim nyias nyias los tswj cov tshuaj nyob rau hauv lub zos concentration.
Nws cov ntshav plasma protein binding tus nqi yog li 44%, sawv cev rau nruab nrab binding peev. Feem ntau cov tshuaj dawb dawb ua kom ruaj khov receptor antagonism, thiab kev siv yeeb tshuaj yuav tsis raug cuam tshuam los ntawm kev sib txuas cov protein ntau.
Nyob rau hauv cov nqe lus ntawm cov metabolism, cov khoom tsis metabolized los ntawm hepatic cytochrome P450 enzyme system. Nws yog tsuas yog degraded mus rau hauv inactive me me-molecule metabolites los ntawm endogenous proteases, uas zoo zam kev siv yeeb tshuaj- tshuaj cuam tshuam txog cov tshuaj hepatic - metabolizing enzymes. Cov yam ntxwv no ua rau nws haum rau cov neeg mob uas muaj kab mob hauv qab uas xav tau cov tshuaj sib xyaw ua ke.
Cov khoom pov thawj zoo ib yam nyob rau hauv vivo clearance profiles, nrog ib tug txhais tau tias plasma clearance ntawm 245 ± 58 mL / min thiab ib nrab tshem tawm ib nrab - lub neej ntawm kwv yees li 1.4 ± 0.4 teev. Nws cov metabolic thiab tshem tawm cov nqi yog nyob ruaj khov, tsis muaj kev pheej hmoo ntawm cov tshuaj tsub zuj zuj. Lub raum ua haujlwm raws li txoj hauv kev loj tshaj tawm: ntau dua 90% ntawm cov tshuaj tau tawm hauv cov zis hauv daim ntawv ntawm cov metabolites tsis ua haujlwm, thaum tsawg dua 10% raug tshem tawm ntawm lub raum raws li cov niam txiv sib xyaw.
Ntawm cov neeg tshwj xeeb, cov neeg mob laus pom tias muaj kev txo qis me ntsis ntawm kev tshem tawm cov tshuaj thiab qhov me me ntawm cov tshuaj raug mob. Tsis muaj kev hloov kho ntau npaum li cas rau cov neeg mob uas mob me mus rau nruab nrab los yog lub raum tsis zoo, thaum siv ceev faj yog pom zoo rau cov neeg mob hnyav lossis lub raum tsis ua haujlwm. Zuag qhia tag nrho, cov khoom muaj txiaj ntsig zoo pharmacokinetic stability.
Nws cov tshuaj synthesis yuav tsum muaj cov khoom siv -theem peptide synthesis (SPPS), nrog cov kauj ruam tseem ceeb xws li kev xaiv cov cab kuj, amino acid txuas, cleavage, thiab purification.
1. Synthetic route design: maj mam ncua ntawm C-kawg mus rau N-terminus
Cov synthesis ua raws li cov tswv yim classic ntawm peptide synthesis - coupling amino acids ib los ntawm ib tug los ntawm C-terminus (carboxyl terminus) mus rau N-terminus (amino terminus). Cov kauj ruam tshwj xeeb yog raws li nram no:
Resin cab kuj xaiv
Feem ntau siv Wang resin los yog HMP resin muaj active hydroxyl pawg ntawm nws nto, uas muaj peev xwm tsim ester daim ntawv cog lus nrog cov carboxyl pawg ntawm cov amino acids kom ua tiav cov khoom -theem anchoring ntawm polypeptide chains. Piv txwv li, ib qho patent siv Fmoc Arg (NO ₂) - Wang resin nrog kev hloov pauv qib ntawm 0.8 mmol / g raws li tus neeg nqa khoom pib, thiab kho thawj cov amino acid (Fmoc Arg (NO ₂) - OH) ntawm cov resin los ntawm cov tshuaj tiv thaiv esterification.
Kev tshem tawm ntawm pawg tiv thaiv Fmoc
Kho cov resin nrog 20% piperidine / DMF tov kom tshem tawm Fmoc tiv thaiv pab pawg ntawm N-qhov kawg ntawm cov amino acids thiab nthuav tawm cov active amino pawg. Piv txwv li, thaum lub sij hawm ua synthesis, nws yog ib qho tsim nyog los xyuas kom meej qhov kev tshem tawm tag nrho ntawm Fmoc pawg los ntawm 10 rov ua "stirring dissolution reaction" cov kauj ruam.
Amino acid coupling ib tug los ntawm ib tug
Conjugate tiv thaiv cov amino acids nyob rau hauv ib ntus, feem ntau yog siv HBTU / HOBt / DIPEA system ua cov coupling reagent. Piv txwv li, nyob rau hauv lub synthesis ntawm etibant resin,icibantNws yog ib qho tsim nyog yuav tsum ua raws li ob peb Fmoc-Oic OH, Fmoc-D-Tic-OH, Fmoc-Ser (tBu) - OH, thiab lwm yam. Tom qab txhua qhov sib txuas, qhov kawg ntawm cov tshuaj tiv thaiv yuav tsum tau kuaj xyuas siv cov txheej txheem indene ketone 9% kom ntseeg tau tias qhov ua tau zoo tshaj 9%.
Cracking thiab deprotection
Tom qab ua tiav tag nrho cov amino acid conjugates, peptide tau cleaved los ntawm cov resin siv ib tug sib tov ntawm trifluoroacetic acid (TFA) thiab lysis buffer (TFA/phenol/TIS/dej{0}}:2.5:0.5), thaum tshem tawm sab saw tiv thaiv pawg (xws li tBu, Pbf, thiab lwm yam). Piv txwv li, nyob rau hauv ib txoj kev, 130.1g ntawm etibant Wang resin reacted ntawm 15℃rau 3 teev, thiab tom qab tawg, 80.2g ntawm crude khoom nrog ib tug purity ntawm 55.0% yog tau.
2. Cov thev naus laus zis tseem ceeb: kev qhia meej ntawm cov amino acids uas tsis yog ntuj tsim
Cov qauv muaj ntau yam tsis yog ntuj amino acids, thiab nws cov synthesis yuav tsum tau daws cov teeb meem hauv qab no:
Taw qhia ntawm D-Tic
D-Tic (octahydroindole-2-carboxylic acid) yog ib qho nyuaj cyclic amino acid, thiab nws cov lus qhia yuav tsum muaj kev sib txuas tshwj xeeb. Piv txwv li, ib qho patent siv Fmoc Ser (tBu) - D-Tic-OH dipeptide fragments rau kev sib txuas, txo qhov tsim ntawm peptide impurities uas ploj lawm (xws li des -D-Tic-etibant).
Thib stereoscopic Control
Thi (thiazole alanine) muaj cov sulfur atoms thiab nws yooj yim rau racemization. Los ntawm optimizing cov coupling reagents (xws li DIC / HOBt) thiab cov tshuaj tiv thaiv kub (chav kub), haiv neeg impurities (xws li D-Thi-ertiban) tuaj yeem tswj tau qis dua 0.03%.
Arg sab saw tiv thaiv
Cov saw hlau sab ntawm arginine muaj cov pab pawg guanidine thiab yuav tsum tau tiv thaiv nrog Pbf lossis TSIS MUAJ ₂ pawg. Piv txwv li, nyob rau hauv cov txheej txheem synthesis, siv Boc-D-Arg (NO ₂) - OPvp raws li cov amino acid kawg tuaj yeem txo cov tiam ntawm peptide impurities uas ploj lawm (xws li des-D-Arg-ertiban).
3. Optimization lub tswv yim: Txhim kho cov txiaj ntsig thiab purity
Dipeptide fragment tswv yim
Ua ntej synthesizing dipeptide fragments (xws li Fmoc Arg (NO ₂) - Pro OH, Fmoc Ser (tBu) - D-Tic-OH) los ntawm ob cov amino acids uas nyob ib sab tuaj yeem txo qis peptide impurities hauv cov kauj ruam txuas. Piv txwv li, ib txoj kev txo cov ntsiab lus impurity tag nrho los ntawm 8.2% mus rau 1.5% los ntawm kev siv dipeptide fragments.
Optimization ntawm cov txheej txheem tawg
Kho cov tshuaj muaj pes tsawg leeg ntawm cov tshuaj cracking (xws li nce qhov feem ntawm phenol) thiab cov tshuaj tiv thaiv lub sij hawm tuaj yeem txhim kho qhov purity ntawm cov khoom nyoos. Piv txwv li, ib qho patent siv cov tshuaj tawg nrog TFA / phenol / TIS / dej =92.5: 2.5: 2.5 los ua kom cov purity ntawm cov khoom nyoos los ntawm 55.0% mus rau 81.7%.
Innovation nyob rau hauv purification txheej txheem
Kev lim dej siv ob- kauj ruam rov qab theem chromatography: thawj kauj ruam siv 0.1% TFA / dej acetonitrile gradient elution, thiab theem thib ob siv 0.15% ammonium acetate tov acetonitrile gradient elution, ua rau purity ntau dua 99.5% ntawm Piv txwv li, ib txoj hauv kev nce cov txiaj ntsig los ntawm 55.2% mus rau 75% los ntawm ob-kauj ruam purification.
4. Daim Ntawv Thov Kev Lag Luam: Ntsuas tus nqi thiab kev ua haujlwm zoo
Resin hloov pauv thiab rov ua dua tshiab
Kev tsim kho qis- cov neeg nqa khoom raug nqi (xws li polystyrene polyethylene glycol copolymer) tuaj yeem txo cov nqi raw khoom. Piv txwv li, ib qho patent siv cov khoom siv rov ua dua tshiab, uas txo tus nqi ntawm ib pawg los ntawm 30%.
Nruam flow synthesis technology
Qhia txog microreactors los yog lub txaj ruaj khov reactors kom ua tiav kev tsim cov amino acid txuas ntxiv thiab ua kom lub voj voog synthesis luv. Piv txwv li, ib qho kev lag luam tau ua kom luv luv ntawm ib qho kev sib xyaw ua ke los ntawm 72 teev mus rau 24 teev los ntawm kev siv thev naus laus zis tsis tu ncua.
Green Chemical Process
Siv cov kuab tshuaj toxicity tsawg (xws li ethyl acetate es tsis txhob dichloromethane) thiab cov catalysts (xws li enzyme catalyzed coupling) kom txo cov pa phem ib puag ncig. Piv txwv li, ib txoj kev tshawb fawb siv lipase catalyzed coupling los txo cov kuab tshuaj los ntawm 50%.
Cov tshuaj synthesis ntawm cov khoom yuav tsum muaj cov khoom siv -theem peptide synthesis technology, uas tsom mus rau cov lus qhia meej ntawm cov amino acids uas tsis yog ntuj tsim, kev ua kom zoo dua ntawm cov kab mob cleavage, thiab kev tsim kho tshiab ntawm cov txheej txheem purification.
Cim npe nrov: icatibant, lwm tus neeg, manufacturers, hoobkas, lag luam wholesale, yuav, nqe, tej, kev muag khoom