Iptacopan
1644670-37-0
422.525, C25H30N2O4
- 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl) benzoic acid
- BENZOIC ACID, 4-((2S,4S)-4-ETHOXY-1-((5-METHOXY-7-METHYL-1H-INDOL-4-YL)METHYL)-2-PIPERIDINYL)-
- Iptacopan
- LNP 023
- LNP-023
- LNP023
- NVP-LNP023
- NVP-LNP023-NX
fda approved, To treat paroxysmal nocturnal hemoglobinuria, 12/5/2023, Fabhalta ‘
Iptacopan is a small-molecule factor B inhibitor previously investigated as a potential treatment for the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH) by inhibiting the complement factor B.1 Factor B is a positive regulator of the alternative complement pathway, where it activates C3 convertase and subsequently C5 convertase.2 This is of particular importance to PNH, where one of the disease hallmarks is the mutation of the PIGA gene. Due to this mutation, all progeny erythrocytes will lack the glycosyl phosphatidylinositol–anchored proteins that normally anchor 2 membrane proteins, CD55 and CD59, that protect blood cells against the alternative complement pathway.3 Additionally, iptacopan has the benefit of targeting factor B, which only affect the alternative complement pathway, leaving the classic and lectin pathway untouched for the body to still mount adequate immune responses against pathogens.2
On December 6th, 2023, Iptacopan under the brand name Fabhalta was approved by the FDA for the treatment of adults with PNH. This approval was based on favorable results obtained from the phase III APPL-PNH and APPOINT-PNH studies, where 82.3% and 77.5% of patients experienced a sustained hemoglobin improvement without transfusions respectively.5
Iptacopan , sold under the brand name Fabhalta, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.[1] It is a complement factor B inhibitor that was developed by Novartis.[1] It is taken by mouth.[1]
Iptacopan was approved by the US Food and Drug Administration (FDA) for the treatment of adults with paroxysmal nocturnal hemoglobinuria in December 2023.[2][3]
Medical uses
Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria.[1][4]
Side effects
The FDA label for iptacopan contains a black box warning for the risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B.[1]
Research
In a clinical study with twelve participants, iptacopan as a single drug led to the normalization of hemolytic markers in most patients, and no serious adverse events occurred during the 12-week study.[5][6]
Iptacopan is also investigated as a drug in other complement-mediated diseases, like age-related macular degeneration and some types of glomerulopathies.[7]
PATENT
https://patents.google.com/patent/US9682968B2/en
Example-26Example-26a4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid ((+) as TFA Salt)
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US411167175&_cid=P12-LQ9ETC-78389-1
Example 1
PAPER
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01870
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.
a Reagents and conditions: (a) i PrMgCl·LiCl, Cbz-Cl, THF; (b) Zn, AcOH; (c) LiBH4, THF; (d) TBDPS-Cl, imidazole, DMF; (e) separation of diastereomers by flash chromatography; (f) TBAF, THF; (g) NaH, EtI, DMF; (h) Ba(OH)2, i PrOH, H2O; (i) K2CO3, MeI, DMF; (j) H2, Pd/C, MeOH; (k) (±)-50, DIPEA, DMA; (l) K2CO3, MeOH; then TMS-diazomethane, toluene, MeOH; (m) chiral SFC; (n) LiOH, H2O, MeOH, THF; (o) (2S,4S)-50, NaBH(OAc)3, DCE.
4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid (41, LNP023). Step 1: tert-Butyl 4-(((2S,4S)-4-Ethoxy-2-(4-(methoxycarbonyl)phenyl)- piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (58). To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl1H-indole-1-carboxylate (57) (1.5 g, 5.18 mmol) and methyl 4- ((2S,4S)-4-ethoxypiperidin-2-yl)benzoate ((2S,4S)-50) (1.185 g, 4.50 mmol) in DCE (20 mL) was added NaBH(OAc)3 (3 g, 14.1 mmol), and this was stirred at rt for 21.5h. Additional tert-butyl 4-formyl-5- methoxy-7-methyl-1H-indole-1-carboxylate (57) (500 mg, 1.90 mmol) was added, and this was stirred for 20 h. The reaction was diluted with EtOAc, washed successively with 5% aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.415 g, quant) which was used without further purification. MS (ESI+) m/z 537.4 (M + H). The absolutestereochemistry was ultimately determined via cocrystallization of 41 with the catalytic domain of FB. Step 2: 4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid (41, LNP023). To a solution of tert-butyl 4-(((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)- piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (58) (2.415 g, 4.50 mmol) in THF (10 mL) and MeOH (20 mL) was added 1 M LiOH in H2O (15 mL, 15 mmol), and this was stirred at 70 °C for 8 h. The reaction was cooled to rt, diluted with H2O, half saturated aqueous KHSO4 and citric acid, saturated with sodium chloride, then extracted with 9:1 DCM/TFE, dried with Na2SO4, filtered, and concentrated. RP-HPLC-B purification provided the title compound (730 mg, 38% for 2 steps). 1 H NMR (400 MHz, D2O) δ 7.96 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 6.66 (s, 1H), 6.20 (s, 1H), 4.62−4.47 (m, 1H), 4.06 (d, J = 13.2 Hz, 1H), 3.97−3.76 (m, 2H), 3.66−3.48 (m, 5H), 3.43−3.29 (m, 1H), 3.26−3.15 (m, 1H), 2.35 (s, 3H), 2.31−2.11 (m, 2H), 2.00 (d, J = 15.4 Hz, 1H), 1.93−1.74 (m, 1H), 1.25−1.07 (m, 3H). HRMS calcd for C25H31N2O4 (M + H)+ 423.2284, found 423.2263. 4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid Hydrochloride (41· HCl). To a solution of 41 (620 mg, 1.47 mmol) in H2O (10 mL) and acetonitrile (3 mL) was added 5 M aqueous HCl (0.5 mL, 2.5 mmol). The mixture was then lyophilized, and the resulting solid was suspended in i PrOH and heated to 70 °C. The mixture turned into a solution after 1.5 h and was then cooled to rt with stirring. After about 5 h, the mixture turned into a suspension and the solid was collected by filtration and dried under high vacuum at 50 °C to provide the title compound as the hydrochloride salt (450 mg, 65%). 1 H NMR (400 MHz, methanol-d4) δ 10.73 (s, 1H), 8.23 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.36−7.31 (m, 1H), 6.77 (s, 1H), 6.42−6.31 (m, 1H), 4.40−4.19 (m, 2H), 3.87−3.80 (m, 1H), 3.76 (s, 3H), 3.68− 3.50 (m, 4H), 3.45−3.38 (m, 1H), 2.51 (s, 3H), 2.30−2.18 (m, 2H), 2.13−1.89 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H). MS (ESI+) m/z 423.3 (M + H).
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Clinical data | |
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Trade names | Fabhalta |
Other names | LNP023 |
AHFS/Drugs.com | Fabhalta |
License data | |
Routes of administration |
By mouth |
Drug class | Complement factor B inhibitor |
ATC code |
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Identifiers | |
CAS Number | |
PubChem CID | |
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PDB ligand | |
Chemical and physical data | |
Formula | C25H30N2O4 |
Molar mass | 422.525 g·mol−1 |
3D model (JSmol) | |
References
- ^ Jump up to:a b c d e f “Fabhalta- iptacopan capsule”. DailyMed. 5 December 2023. Archived from the original on 10 December 2023. Retrieved 10 December 2023.
- ^ “Novartis receives FDA approval for Fabhalta (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH”. Novartis (Press release). Archived from the original on 12 December 2023. Retrieved 6 December 2023.
- ^ “Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 6 December 2023. Archived from the original on 21 January 2023. Retrieved 10 December 2023.
- ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/218276Orig1s000ltr.pdf Archived 10 December 2023 at the Wayback Machine This article incorporates text from this source, which is in the public domain.
- ^ Jang JH, Wong L, Ko BS, Yoon SS, Li K, Baltcheva I, et al. (August 2022). “Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study”. Blood Advances. 6 (15): 4450–4460. doi:10.1182/bloodadvances.2022006960. PMC 9636331. PMID 35561315.
- ^ “Novartis Phase III APPOINT-PNH trial shows investigational oral monotherapy iptacopan improves hemoglobin to near-normal levels, leading to transfusion independence in all treatment-naïve PNH patients”. Novartis (Press release). Archived from the original on 12 December 2023. Retrieved 6 September 2023.
- ^ Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, et al. (April 2019). “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases”. Proceedings of the National Academy of Sciences of the United States of America. 116 (16): 7926–7931. Bibcode:2019PNAS..116.7926S. doi:10.1073/pnas.1820892116. PMC 6475383. PMID 30926668.
External links
- Clinical trial number NCT04558918 for “Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment (APPLY-PNH)” at ClinicalTrials.gov
- Clinical trial number NCT04820530 for “Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy (APPOINT-PNH)” at ClinicalTrials.gov
///////Iptacopan, fda 2023, approvals, 2023, paroxysmal nocturnal hemoglobinuria, 12/5/2023, Fabhalta , LNP 023, LNP-023, LNP023, NVP-LNP023, NVP-LNP023-NX