Iptacopan

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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

US9682968

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)

A mixture of methyl 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoate, Intermediate 6-2b peak-1 (tr=1.9 min), (84 mg, 0.192 mmol) and LiOH in H₂O (1 mL, 1 mmol) in THF (1 mL)/MeOH (2 mL) was stirred at room temperature for 16 h, and then concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. Absolute stereochemistry was determined by comparison with enantiopure synthesis in Example-26c. ¹H NMR (TFA salt, 400 MHz, D₂O) δ 8.12 (d, J=8.19 Hz, 2H), 7.66 (br. d, J=8.20 Hz, 2H), 7.35 (d, J=3.06 Hz, 1H), 6.67 (s, 1H), 6.25 (d, J=3.06 Hz, 1H), 4.65 (dd, J=4.28, 11.49 Hz, 1H), 4.04 (d, J=13.00 Hz, 1H), 3.87-3.98 (m, 2H), 3.53-3.69 (m, 5H), 3.38-3.50 (m, 1H), 3.20-3.35 (m, 1H), 2.40 (s, 3H), 2.17-2.33 (m, 2H), 2.08 (br. d, J=15.70 Hz, 1H), 1.82-1.99 (m, 1H), 1.28 (t, J=7.03 Hz, 3H); HRMS calcd. for C₂₆H₃₁N₂O₃(M+H)⁺423.2284, found 423.2263.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US411167175&_cid=P12-LQ9ETC-78389-1

Example 1

Intermediate 1:

(MOL) (CDX)

To a 3 L three-necked flask were successively added tetrahydrofuran (150 mL) and 4-bromoxynil (50 g). Isopropylmagnesium chloride lithium chloride coordination complex (1.3 M, 210 mL) was slowly added to the reaction system under nitrogen atmosphere. After the reaction was carried out at room temperature for 2 h, the reaction system was diluted with anhydrous tetrahydrofuran (500 mL) for dilution. The reaction system was cooled to −5° C., and 4-methoxypyridine (25 mL) was added, followed by slowly dropwise addition of benzyl chloroformate (35 mL) (the system temperature was maintained below 0° C.). After the dropwise addition was completed, the reaction system was successively reacted at 0° C. for 2 h, and then warmed to room temperature and reacted at that temperature for 16 h. After the reaction was completed, hydrochloric acid solution (6 M, 150 mL) was added. The mixture was stirred at room temperature for half an hour, added with water (1000 mL) for dilution, and extracted twice with ethyl acetate (500 mL). The extract phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting crude product was separated and purified by a silica gel column (petroleum ether:ethyl acetate=3:1 to 1:1) to give intermediate 1 (23 g, yield: 23%). MS m/z (ESI): 333.0 [M+H].

Intermediate 2:

(MOL) (CDX)

To a 500 mL single-neck flask were successively added intermediate 1 (28 g), zinc powder (55 g) and acetic acid (200 mL). The reaction mixture was heated to 100° C. and reacted at that temperature for 16 h. After the reaction was completed, the reaction mixture was filtered. The filtrate was added with water (500 mL) for dilution and extracted with ethyl acetate (500 mL). The extract phase was washed twice with saturated aqueous sodium bicarbonate solution (500 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 2 (26 g, yield: 73%). MS m/z (ESI): 334.8 [M+H].

Intermediate 3:

(MOL) (CDX)

To a 1 L single-neck flask were successively added tetrahydrofuran (100 mL), ethanol (100 mL) and intermediate 2 (26 g), and sodium borohydride (2 g) was added in batches. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the system was cooled to 0° C., and saturated aqueous ammonium chloride solution (100 mL) was added until the temperature did not increase any more. Water (300 mL) was added for dilution, followed by extraction with ethyl acetate (200 mL×2). The extract phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 3 (25 g, yield: 76%). MS m/z (ESI): 336.9 [M+H].

Intermediate 4:

(MOL) (CDX)

Dichloromethane (200 mL) was added to a 500 mL single-neck flask, and then intermediate 3 (25 g), imidazole (6.6 g) and tert-butyldiphenylchlorosilane (25 g) were successively added. The mixture was reacted at room temperature for 2 h. After the reaction was completed, water (500 mL) was added for dilution, followed by the extraction with dichloromethane (200 mL). The extract phase was washed with water (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=10:1) to give intermediate 4 (5.7 g, yield: 13%, R _f=0.55; isomer R _f=0.50). MS m/z (ESI): 597.0 [M+23].

Intermediate 5:

(MOL) (CDX)

To a 250 mL single-neck flask were successively added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 30 mL) and intermediate 4 (5 g). The mixture was reacted at room temperature for 2 h. After the reaction was completed, water (100 mL) was added for dilution, followed by the extraction with ethyl acetate (50 mL×3). The extract phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=3:1 to 0:1) to give a racemic intermediate. The intermediate was subjected to SFC chiral resolution (apparatus: SFC Thar prep 80; column: CHIRALPAK AD-H, 250 mm×20 mm, 5 m; modifier: 35% methanol (0.2% aqueous ammonia); column temperature: 40° C.; column pressure: 60 bar; wavelength: 214/254 nm; flow rate: 40 g/min; Rt=4.78 min) to give intermediate 5 (1.2 g, yield: 41%). MS m/z (ESI): 358.8 [M+23].

Intermediate 6:

(MOL) (CDX)

To a 100 mL single-neck flask were successively added N,N-dimethylformamide (15 mL) as a solvent, intermediate 5 (1.2 g) and iodoethane (1.1 g). After the reaction system was cooled to 0° C., sodium hydrogen (60%, 243 mg) was added. Then the system was warmed to room temperature and reacted at that temperature for 2 h. After the reaction was completed, water (30 mL) was added for dilution, followed by the extraction with ethyl acetate (50 mL). The extract phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 6 (1.2 g, yield: 83%). MS m/z (ESI): 386.9 [M+23].

Intermediate 7:

(MOL) (CDX)

To a 100 mL single-neck flask were successively added methanol (10 mL), water (10 mL), concentrated sulfuric acid (10 mL) and intermediate 6 (1.2 g). The mixture was heated to 80° C. and reacted at that temperature for 48 h. After the reaction was completed, the reaction mixture was concentrated to remove methanol. The residue was made neutral with saturated aqueous sodium hydroxide solution and extracted three times with ethyl acetate (10 mL). The extract phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 7 (850 mg, yield: 81%). MS m/z (ESI): 264.1 [M+H]. ¹H NMR (400 MHz, CDCl ₃) δ 8.01 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.13 (dd, J=11.7, 2.4 Hz, 1H), 3.92 (s, 3H), 3.82-3.70 (m, 1H), 3.62-3.47 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.88 (m, 1H), 2.07-1.97 (m, 1H), 1.95-1.85 (m, 1H), 1.82-1.62 (m, 2H), 1.27 (t, J=7.0 Hz, 3H).

Intermediate 8:

(MOL) (CDX)

To a 250 mL single-neck flask were successively added dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), BOC anhydride (5.68 g), 4-dimethylaminopyridine (227 mg) and triethylamine (2.26 g). The mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution (5 mL) and extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to give intermediate 8 (4.6 g, yield: 94%). MS m/z (ESI): 262.0 [M+H].

Intermediate 9:

(MOL) (CDX)

To a 250 mL single-neck flask were successively added dichloromethane (80 mL), N-methylformanilide (3.8 g) and oxalyl chloride (3.6 g). The mixture was stirred at room temperature for 3 h. Then the reaction temperature was lowered to −14° C., and intermediate 8 (2.5 g) was added. The reaction system was naturally warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction liquid was poured into ice water and extracted three times with dichloromethane (100 mL). The combined extract phases were washed twice with water (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=20:1) to give intermediate 9 (1.3 g, yield: 47%). MS m/z (ESI): 290.0 [M+H]. ¹H NMR (400 MHz, CDCl ₃) δ 10.65 (s, 1H), 7.65 (d, J=3.4 Hz, 1H), 7.49 (d, J=3.4 Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

Intermediate 10:

(MOL) (CDX)

To a 50 mL three-necked flask were successively added 1,2-dichloroethane (5 mL), intermediate 7 (127 mg) and intermediate 9 (130 mg). The mixture was reacted at room temperature for 18 h. Then sodium triacetoxyborohydride (438.72 mg) was added, and the system was successively reacted at room temperature for 18 h. After the reaction was completed, dichloromethane (10 mL) was added for dilution, followed by a wash with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was separated and purified by a silica gel column (methanol:dichloromethane=1:10) to give intermediate 10 (50 mg, yield: 14.58%). MS m/z (ESI): 437.3 [M+H], RT=1.142 min.

Intermediate 11:

(MOL) (CDX)

To a 50 mL three-necked flask were successively added tetrahydrofuran (0.5 mL), methanol (0.5 mL), water (0.5 mL), sodium hydroxide (44 mg) and intermediate 10 (50 mg). The mixture was reacted at room temperature for 18 h. After the reaction was completed, the reaction liquid was directly concentrated under reduced pressure and lyophilized to give intermediate 11 (50 mg, yield: 92%). MS m/z (ESI): 423.1 [M+H].

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.

Abstract Image

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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Iptacopan
Clinical data


Trade names	Fabhalta
Other names	LNP023
AHFS/Drugs.com	Fabhalta
License data	US DailyMed: Iptacopan
Routes of administration	By mouth
Drug class	Complement factor B inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1644670-37-0
PubChem CID	90467622
DrugBank	DB16200
ChemSpider	75533872
UNII	8E05T07Z6W
KEGG	D12251 D12252
ChEMBL	ChEMBL4594448
PDB ligand	JGQ (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₅H₃₀N₂O₄
Molar mass	422.525 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

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

It's only fair to share...

Iptacopan

Iptacopan

Medical uses

Side effects

Research

Example 1

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References

External links

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