| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
Transthyretin (TTR) mRNA. Inotersen binds to the TTR mRNA transcript with high affinity and specificity, forming an DNA-RNA heteroduplex that recruits RNase H1. RNase H1 cleaves the RNA strand, leading to degradation of TTR mRNA and reduction of TTR protein synthesis.
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|---|---|
| ln Vitro |
TTR mRNA levels in HepG2 cells are dose-dependently decreased by inotersen sodium (0.16–20 μM; 16 h)[1].
In vitro, inotersen shows potent and selective reduction of TTR mRNA in human hepatoma cell lines (e.g., HepG2, HuH-7) and primary human hepatocytes with an IC50 in the low nanomolar range. No significant off-target effects on other mRNA species are observed at concentrations up to 10 uM. |
| ln Vivo |
In transgenic mice carrying the Ile84Ser human TTR mutant, inotersen sodium (10–100 mg/kg; sc twice a week for 4 weeks) decreases the plasma TTR protein by >80%[1].
In vivo, inotersen produced dose-dependent and sustained reduction of serum TTR protein in mice, rats, and cynomolgus monkeys following subcutaneous administration. In Phase 3 clinical trials, inotersen (300 mg SC weekly) achieved mean TTR reductions of approximately 70-80% in patients with hATTR amyloidosis. |
| Enzyme Assay |
No specific cell-free binding assays are applicable as inotersen is an antisense oligonucleotide. Target engagement is assessed via TTR mRNA knockdown. For binding affinity studies, surface plasmon resonance (SPR) can be used to measure the hybridization affinity of inotersen to a complementary TTR mRNA oligonucleotide sequence.
|
| Cell Assay |
Human hepatoma cells (HepG2 or HuH-7) are seeded and treated with inotersen at concentrations ranging from 0.1 nM to 10 uM for 24-72 hours. TTR mRNA levels are measured by quantitative RT-PCR. TTR protein secreted into culture medium is quantified by ELISA. To assess RNase H1-dependent activity, a cell-free RNase H1 cleavage assay using TTR mRNA and the antisense oligonucleotide can be performed.
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| Animal Protocol |
Transgenic mice expressing human TTR are administered inotersen via subcutaneous injection at doses of 5-50 mg/kg once weekly. Blood samples are collected at baseline and weekly intervals to measure serum TTR levels by ELISA. Liver tissue is collected at the end of the study for TTR mRNA quantification and histopathological assessment. Non-human primate studies (cynomolgus monkeys) are also conducted to assess TTR lowering efficacy.
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| ADME/Pharmacokinetics |
PK: terminal elimination half-life 32.3 days (range 29.4-35.5 days); total body clearance 3.18 L/h (range 3.08-3.29 L/h); volume of distribution 293 L; plasma protein binding greater than 94%; median Tmax 2-4 hours following SC administration; primarily cleared through metabolism (endonuclease exonuclease degradation).
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| Toxicity/Toxicokinetics |
Toxicology studies in animals (mice, rats, monkeys) showed an acceptable safety profile. In humans, the most significant adverse events are glomerulonephritis (immune complex-mediated) and thrombocytopenia. Due to these risks, inotersen is available only through a Risk Evaluation and Mitigation Strategy (REMS) program requiring regular monitoring of platelet counts and renal function.
|
| References |
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| Additional Infomation |
See also: Sodium Inotersen (note moved to).
Drug Indications Treatment of stage 1 or 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). Other information: Inotersen (Tegsedi) is approved for the treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR). The recommended dosing is 300 mg once weekly by subcutaneous injection. It was approved by EMA in 2018 and FDA in 2018, with a boxed warning for thrombocytopenia and glomerulonephritis. |
| Molecular Formula |
C230H299N69NA19O121P19S19
|
|---|---|
| Molecular Weight |
7600.76688694954
|
| Exact Mass |
7597.719
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| CAS # |
1432726-13-0
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| Related CAS # |
Inotersen;1492984-65-2
|
| PubChem CID |
121493436
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
25
|
| Hydrogen Bond Acceptor Count |
166
|
| Rotatable Bond Count |
156
|
| Heavy Atom Count |
477
|
| Complexity |
20100
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| Defined Atom Stereocenter Count |
70
|
| SMILES |
S=P([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C=NC3C(NC(N)=NC2=3)=O)O1)OCCOC)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(NC(N)=NC2=3)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C(NC(C(C)=C2)=O)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C(NC(C(C)=C2)=O)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(N)=NC=NC2=3)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C(N=C(C(C)=C2)N)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(N)=NC=NC2=3)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C(NC(C(C)=C2)=O)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(NC(N)=NC2=3)=O)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(N)=NC=NC2=3)O1)OP([O-])(OC[C@@H]1[C@H](C[C@H](N2C=NC3C(N)=NC=NC2=3)O1)OP([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C=NC3C(N)=NC=NC2=3)O1)OCCOC)OP([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C(NC(C(C)=C2)=O)=O)O1)OCCOC)OP([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C(N=C(C(C)=C2)N)=O)O1)OCCOC)OP([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C(N=C(C(C)=C2)N)=O)O1)OCCOC)OP([O-])(OC[C@@H]1[C@H]([C@H]([C@H](N2C(N=C(C(C)=C2)N)=O)O1)OCCOC)O)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)=S)O[C@@H]1[C@@H](COP([O-])(O[C@@H]2[C@@H](COP(=O)(O[C@@H]3[C@@H](COP([O-])(O[C@@H]4[C@@H](CO)O[C@H]([C@@H]4OCCOC)N4C(NC(C(C)=C4)=O)=O)=S)O[C@H]([C@@H]3OCCOC)N3C(N=C(C(C)=C3)N)=O)[S-])O[C@H]([C@@H]2OCCOC)N2C(NC(C(C)=C2)=O)=O)=S)O[C@H]([C@@H]1OCCOC)N1C(NC(C(C)=C1)=O)=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]
|
| InChi Key |
QHNLHIXTRPKKQN-QKZXOKHWSA-A
|
| InChi Code |
InChI=1S/C230H318N69O121P19S19.19Na/c1-98-53-280(219(312)262-178(98)231)140-43-110(121(382-140)66-364-425(328,444)406-114-47-144(292-90-254-150-183(236)244-85-249-188(150)292)387-126(114)71-368-423(326,442)404-112-45-142(282-59-104(7)197(303)274-225(282)318)383-122(112)67-363-421(324,440)403-111-44-141(281-58-103(6)196(302)273-224(281)317)385-124(111)69-366-427(330,446)410-119-52-149(297-95-260-156-194(297)268-217(242)271-204(156)310)391-130(119)75-372-431(334,450)419-167-139(401-215(177(167)362-42-32-352-22)299-97-261-157-195(299)269-218(243)272-205(157)311)84-381-438(341,457)418-165-136(398-213(175(165)360-40-30-350-20)291-64-109(12)202(308)279-230(291)323)82-379-437(340,456)417-163-135(397-211(173(163)358-38-28-348-18)289-62-107(10)200(306)277-228(289)321)81-378-435(338,454)414-161-132(394-209(171(161)356-36-26-346-16)286-56-101(4)181(234)265-222(286)315)78-375-433(336,452)412-159-120(65-300)392-207(169(159)354-34-24-344-14)288-61-106(9)199(305)276-227(288)320)402-422(325,441)367-70-125-115(48-145(386-125)293-91-255-151-184(237)245-86-250-189(151)293)407-426(329,445)365-68-123-113(46-143(384-123)283-60-105(8)198(304)275-226(283)319)405-424(327,443)371-74-129-118(51-148(390-129)296-94-259-155-193(296)267-216(241)270-203(155)309)409-429(332,448)370-72-127-116(49-146(388-127)294-92-256-152-185(238)246-87-251-190(152)294)408-428(331,447)369-73-128-117(50-147(389-128)295-93-257-153-186(239)247-88-252-191(153)295)411-430(333,449)374-77-138-166(176(361-41-31-351-21)214(400-138)298-96-258-154-187(240)248-89-253-192(154)298)420-439(342,458)380-83-137-164(174(359-39-29-349-19)212(399-137)290-63-108(11)201(307)278-229(290)322)416-436(339,455)377-80-134-162(172(357-37-27-347-17)210(396-134)287-57-102(5)182(235)266-223(287)316)415-434(337,453)376-79-133-160(170(355-35-25-345-15)208(395-133)285-55-100(3)180(233)264-221(285)314)413-432(335,451)373-76-131-158(301)168(353-33-23-343-13)206(393-131)284-54-99(2)179(232)263-220(284)313;;;;;;;;;;;;;;;;;;;/h53-64,85-97,110-149,158-177,206-215,300-301H,23-52,65-84H2,1-22H3,(H,324,440)(H,325,441)(H,326,442)(H,327,443)(H,328,444)(H,329,445)(H,330,446)(H,331,447)(H,332,448)(H,333,449)(H,334,450)(H,335,451)(H,336,452)(H,337,453)(H,338,454)(H,339,455)(H,340,456)(H,341,457)(H,342,458)(H2,231,262,312)(H2,232,263,313)(H2,233,264,314)(H2,234,265,315)(H2,235,266,316)(H2,236,244,249)(H2,237,245,250)(H2,238,246,251)(H2,239,247,252)(H2,240,248,253)(H,273,302,317)(H,274,303,318)(H,275,304,319)(H,276,305,320)(H,277,306,321)(H,278,307,322)(H,279,308,323)(H3,241,267,270,309)(H3,242,268,271,310)(H3,243,269,272,311);;;;;;;;;;;;;;;;;;;/q;19*+1/p-19/t110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120+,121+,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,145+,146+,147+,148+,149+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,206+,207+,208+,209+,210+,211+,212+,213+,214+,215+,421?,422?,423?,424?,425?,426?,427?,428?,429?,430?,431?,432?,433?,434?,435?,436?,437?,438?,439?;;;;;;;;;;;;;;;;;;;/m0.................../s1
|
| Chemical Name |
nonadecasodium;1-[(2R,4S,5R)-4-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-hydroxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxyoxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-oxidophosphinothioyl]oxy-5-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3R,4R,5R)-2-[[[(2R,3R,4R,5R)-2-[[[(2R,3R,4R,5R)-2-[[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-2-[[[(2R,3R,4R,5R)-2-(hydroxymethyl)-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]-4-(2-methoxyethoxy)oxolan-3-yl]oxy-sulfidophosphoryl]oxymethyl]-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-oxidophosphinothioyl]oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O: 100 mg/mL (13.16 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (13.16 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1316 mL | 0.6578 mL | 1.3157 mL | |
| 5 mM | 0.0263 mL | 0.1316 mL | 0.2631 mL | |
| 10 mM | 0.0132 mL | 0.0658 mL | 0.1316 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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