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Iptacopan (LNP-023; LNP023) HCl, the hydrochloride salt of Iptacopan, is an oral, potent and selective factor B inhibitor ( IC50 = 10 nM). It has the potential for Treating a Diverse Array of Complement Mediated Diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases, as the alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of these diseases. Iptacopan (Fabhalta) was approved in 2023 by FDA for treating Paroxysmal nocturnal haemoglobinuria.
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| ln Vitro |
LNP023 significantly suppresses alternative complement pathway (AP)-induced membrane attack complex (MAC) production in human serum by 50% (IC50 value 130 nM) [2]. LNP023 demonstrates high selectivity against other proteases, with IC50 values >30 μM among a panel of 41 human proteases, including AP protein factor D (>100 μM) [3].
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| ln Vivo |
LNP023 (20-180 mg/kg; oral dose) inhibits KRN (150 μL)-induced arthritis in mice and is efficacious in a rat experimental model of membranous nephropathy via preventive and therapeutic dosing [2]. LNP023 has an intermediate half-life (T1/2; 3.4 hours in Wistar Han rats and 5.5 hours in Beagle dogs) and Cmax (410 nM in Wistar Han rats and 2200 nM in Beagle dogs) following oral treatment (30 in rats and 10 in dogs). mg/kg)[3]. Due to high plasma clearance (8 and 2 mL/min/kg), LNP023 demonstrates a terminal elimination half-life (T1/2; 7 hours in Wistar Han rats, 5.6 hours in Beagle dogs) with a broad distribution after intravenous injection, respectively. volumes (2.3 and 0.6 L/kg, respectively) combined (rat 1.0 and dog 0.1 mg/kg) [3].
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| Enzyme Assay |
In Vitro Inhibition Assays [2].
Compounds were tested for FB inhibition either by using CVF:Bb as stable surrogate of the C3 convertase and purified endogenous C3 as substrate or by using a competition binding assay with FB and a Cy5-labeled small-molecule inhibitor as probe. AP inhibition was measured in 50% human serum or 50% human whole blood by following zymosan A-induced MAC formation. Serum or whole blood was preincubated with compound for 30 min before transfer to zymosan A-coated plates. MAC formation was detected with an anti-C9 neoepitope antibody by ELISA. AP complement deposition in mouse serum was measured in an analogous way except that C3b deposition was detected instead of MAC formation. Further details on protein purification and all in vitro assays are given in SI Appendix. |
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| Animal Protocol |
Animal/Disease Models: C57BL/6 mice with KRN-induced arthritis[2]
Doses: 20, 60, and 180 mg/kg Route of Administration: Orally gavaged; twice a day (bid) for 14 days Experimental Results: Blocked KRN-induced arthritis. |
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| References |
[1]. Dimitrios C Mastellos, et al. Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol. 2018 Jul;55(3):167-175.
[2]. Anna Schubart, et al. Small-molecule Factor B Inhibitor for the Treatment of Complement-Mediated Diseases. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931. [3]. Nello Mainolfi, et al. Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases. J Med Chem. 2020 Jun 11;63(11):5697-5722. |
| Molecular Formula |
C25H31CLN2O4
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|---|---|
| Molecular Weight |
458.98
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| Exact Mass |
458.20
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| Elemental Analysis |
C, 65.42; H, 6.81; Cl, 7.72; N, 6.10; O, 13.94
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| CAS # |
1646321-63-2
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| Related CAS # |
1646321-63-2 (HCl); 1644670-37-0; 1644670-38-1 (TFA)
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| Appearance |
White to off-white solid powder
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| tPSA |
74.8Ų
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| SMILES |
Cl[H].O(C([H])([H])C([H])([H])[H])[C@@]1([H])C([H])([H])C([H])([H])N(C([H])([H])C2=C(C([H])=C(C([H])([H])[H])C3=C2C([H])=C([H])N3[H])OC([H])([H])[H])[C@]([H])(C2C([H])=C([H])C(C(=O)O[H])=C([H])C=2[H])C1([H])[H]
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| InChi Key |
SEZXOFFLNHXEJE-CQERKEQDSA-N
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| InChi Code |
InChI=1S/C25H30N2O4.ClH/c1-4-31-19-10-12-27(22(14-19)17-5-7-18(8-6-17)25(28)29)15-21-20-9-11-26-24(20)16(2)13-23(21)30-3;/h5-9,11,13,19,22,26H,4,10,12,14-15H2,1-3H3,(H,28,29);1H/t19-,22-;/m0./s1
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| Chemical Name |
4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid hydrochloride
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| Synonyms |
LNP023 hydrochloride; Iptacopan; LNP-023 hydrochloride; LNP 023 hydrochloride; LNP 023 HCL; LNP-023 HCL; LNP023 HCL; Fabhalta
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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, 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) |
DMSO : ~250 mg/mL (~544.69 mM)
H2O : ~50 mg/mL (~108.94 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1787 mL | 10.8937 mL | 21.7874 mL | |
| 5 mM | 0.4357 mL | 2.1787 mL | 4.3575 mL | |
| 10 mM | 0.2179 mL | 1.0894 mL | 2.1787 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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