Sebetralstat

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Sebetralstat, KVD 900

CAS 1933514-13-6

491.5 g/mol

O5ZD2TU2B7

FDA 7/3/2025, Ekterly, To treat acute attacks of hereditary angioedema

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide

Sebetralstat, sold under the brand name Ekterly, is a medication used for the treatment of hereditary angioedema.^[1] Sebetralstat is a plasma kallikrein inhibitor.^[1]

Sebetralstat was approved for medical use in the United States in July 2025.^[1]^[2]

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00921

^aReagents and conditions: (a) 2-Hydroxypyridine (1.2 equiv), K₂CO₃ (3.0 equiv), acetone, 50 °C, 18 h, 78%; (b) methanesulfonyl chloride (1.3 equiv), Et₃N, (1.4 equiv), dichloromethane, rt, 18h, 93%; (c) methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (0.83 equiv), K₂CO₃ (2.0 equiv), DMF, 60 °C, 18 h, 54%; (d) NaOH (3.0 equiv), THF-MeOH-H₂O, rt, 18 h, 34%; (e) 22a (1.0 equiv), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (1.0 equiv), HATU (1.1 equiv), Et₃N (6.0 equiv), dichloromethane, rt, 4 h, 64%.

Synthesis of Sebetralstat

1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (19)

4-(Chloromethyl)benzyl alcohol 18 (5.0 g, 31.9 mmol) was added to a solution of potassium carbonate (13.2 g, 96 mmol) and 2-hydroxypyridine (3.6 g, 38.3 mmol) in acetone (250 mL). The reaction mixture was heated at 50 °C for 18 h and then concentrated in vacuo. The residue was partitioned between dichloromethane (300 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica (0–10% methanol in dichloromethane) to afford 19 (5.4 g, 25.1 mmol, 78% yield) as a white solid. MS (ESI) m/z 216.0 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.34–7.21 (m, 4H), 6.41 (dd, J = 9.1, 1.3 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.15 (t, J = 5.7 Hz, 1H), 5.07 (s, 2H), 4.46 (d, J = 5.7 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 161.4, 141.9, 140.0, 139.0, 135.7, 127.5, 126.6, 119.8, 105.4, 62.6, 50.8.

1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one (20)

A reaction flask containing 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (19) (8.45 g, 39.3 mmol), dry dichloromethane (80 mL), and triethylamine (7.66 mL, 55.0 mmol) was cooled in an ice–water bath. Methanesulfonyl chloride (3.95 mL, 51.0 mmol) was added to the reaction at 0 °C, and ice–water bath cooling continued. After 15 min, the ice–water bath was removed and stirring continued at room temperature overnight. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with further dichloromethane (2 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford 20 (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid. MS (ESI) m/z 234.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.49–7.39 (m, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.42 (ddd, J = 9.2, 1.3, 0.7 Hz, 1H), 6.24 (td, J = 6.7, 1.4 Hz, 1H), 5.09 (s, 2H), 4.73 (s, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.4, 140.1, 139.1, 137.6, 136.9, 129.0, 127.9, 119.9, 105.5, 50.8, 45.8.

Methyl 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21a) and Methyl 5-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21b)

Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.11 g, 11.77 mmol; CAS No. 318496-66-1) was added to a solution of potassium carbonate (3.25 g, 23.54 mmol) and 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one 20 (3.30 g, 14.12 mmol) in N,N-dimethylformamide (5 mL) and heated at 70 °C for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 × 100 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (120 g column, 0–100% (10% ethanol in ethyl acetate) in isohexanes to afford two regioisomers: 21a (2.03 g, 5.47 mmol, 47% yield) as an off-white solid and 21b (350 mg, 0.92 mmol, 8% yield). 21a MS (ESI) m/z 368.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.41 (ddd, J = 8.9, 6.5, 2.1 Hz, 1H), 7.25 (d, J = 1.2 Hz, 4H), 6.40 (dt, J = 9.1, 1.0 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.49 (s, 2H), 3.72 (s, 3H), 3.23 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 163.2, 161.8, 150.5, 140.6, 139.6, 137.6, 136.3, 135.6, 128.5, 128.4, 120.3, 111.8, 106.0, 66.0, 58.0, 55.1, 51.5, 51.2. 21b MS (ESI) m/z 368.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.28–7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.43–6.36 (m, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.35 (s, 2H), 5.06 (s, 2H), 4.78 (s, 2H), 3.75 (s, 3H), 3.25 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 163.4, 161.8, 142.4, 140.9, 140.5, 139.6, 137.4, 136.2, 128.3, 120.3, 112.8, 106.0, 61.7, 58.2, 53.0, 51.7, 51.2.

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (22a)

To methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate 21a (3.77 g, 10.26 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (15.39 mL, 30.80 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1 M aqueous HCl solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 22a (1.22 g, 3.45 mmol, 34% yield) as a white solid. MS (ESI) m/z 354.2 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.32 (s, 1H), 7.76 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.30–7.20 (m, 4H), 6.40 (ddd, J = 9.1, 1.4, 0.7 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.50 (s, 2H), 3.22 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 164.3, 161.8, 150.5, 140.6, 139.6, 137.6, 136.4, 135.6, 128.5, 128.4, 120.3, 113.0, 106.0, 66.0, 58.0, 55.1, 51.2.

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic Acid (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-amide (14w)

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid 22a (75 mg, 0.212 mmol), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (49 mg, 0.212 mmol; CAS No. 1256812-75-5), and HATU (89 mg, 0.233 mmol) were suspended in anhydrous dichloromethane (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated, and then left to stir at room temperature for 4 h. The solvent was removed under reduced pressure, and the resulting residue was quenched with saturated aqueous ammonium chloride solution (5 mL). An off-white solid resulted, which was sonicated, filtered under reduced pressure, washed with water, and dried in a vacuum oven at 40 °C overnight. The residue was purified by chromatography eluting with 1% NH₃ in MeOH/dichloromethane to afford 14w as a white solid (67 mg, 64% yield). MS (ESI) m/z 492.0 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.42 (t, J = 5.4 Hz, 1H), 8.29–8.21 (m, 2H), 7.75 (ddd, J = 0.7, 2.1, 6.8 Hz, 1H), 7.41 (ddd, J = 2.1, 6.6, 8.9 Hz,1H), 7.28–7.17 (m, 5H), 6.39 (ddd, J = 0.7, 1.4, 9.2 Hz, 1H), 6.22 (td, J = 1.4, 6.7 Hz, 1H), 5.28 (s, 2H), 5.07 (s, 2H), 4.57–4.46 (m, 4H), 3.92 (s, 3H), 3.25 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9, 161.3, 153.0 (J_C–F = 8.7 Hz), 147.5, 146.8 (J_C–F = 253.5 Hz), 146.0 (J_C–F = 7.2 Hz), 145.2 (J_C–F = 11.6 Hz), 140.1, 139.1, 137.1, 136.0, 133.2, 128.1, 127.9, 119.9, 116.3, 108.7, 105.5, 66.3, 57.5, 56.4, 54.6, 50.7, 38.3.

PATENT

US10364238,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US232820883&_cid=P22-MCYEU3-92408-1

Example 41

3-Fluoro-4-methoxy-pyridine-2-carbonitrile

To a large microwave vial, cyanocopper (1.304 g, 14.56 mmol) was added to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100° C. for 16 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and required additional water (40 mL) and EtOAc (2×50 mL) with sonication to break-up the solid precipitated. The combined layers were filtered through a plug of celite and the organic layer isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a pale green solid identified as the desired compound 3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield)

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester

3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled in an ice-salt bath to −5° C. and then sodium borohydride (153 mg, 4.05 mmol) was added portionwise maintaining the reaction temperature ˜0° C. The deep brown solution was left to stir at 0° C. and slowly allowed to warm to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40° C. to afford a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (10 mL). An emulsion formed so the organics were separated via a phase separating cartridge and concentrated. The crude liquid was purified by chromatography eluting with EtOAc/iso-Hexane to afford the title compound, (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62% yield)

[MH] ⁺=257

C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt and left to stir at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and then triturated with ether, sonicated and then decanted to give a cream coloured solid (75 mg, 55% yield) identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt.

[MH] ⁺=157

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (75 mg, 0.212 mmol), C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt (49 mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were suspended in anhydrous DCM (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated and then left to stir at rt for 4 hours. The solvent was removed under reduced pressure and the resulting residue was quenched with ammonium chloride solution (5 mL). An off white solid resulted which was sonicated, filtered under reduced pressure washed with water and then placed in the vac oven at 40° C. overnight. The crude material was purified by chromatography eluting with (1% ammonia-methanol)/DCM to afford the 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide as a white solid (67 mg, 64% yield)

[MH] ⁺=492

NMR (d ⁶-DMSO) δ: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J=1.4, 6.7 Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9 Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.8 Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J=5.4 Hz)

Medical uses

Sebetralstat is indicated for the treatment of acute attacks of hereditary angioedema.^[1]

Pharmacology

Sebetralstat is a plasma kallikrein inhibitor that contains the unusual 2-pyridone heterocycle.^[3]

Society and culture

Legal status

Sebetralstat was approved for medical use in the United States in July 2025.^[1] The US Food and Drug Administration granted the application for sebetralstat orphan drug designation.^[4]

Names

Sebetralstat is the international nonproprietary name.^[5]

Sebetralstat is sold under the brand name Ekterly.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Ekterly- sebetralstat tablet”. DailyMed. 7 July 2025. Retrieved 9 July 2025.
^ “KalVista Pharmaceuticals Announces FDA Approval of Ekterly (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema” (Press release). Kalvista. 7 July 2025. Retrieved 9 July 2025 – via Business Wire.
^ Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, et al. (October 2022). “Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema”. Journal of Medicinal Chemistry. 65 (20): 13629–13644. doi:10.1021/acs.jmedchem.2c00921. PMC 9620001. PMID 36251573.
^ “Sebetralstat Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 9 July 2025.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.

External links

“Sebetralstat (Code – C184930)”. EVS Explore.
Clinical trial number NCT05259917 for “A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)” at ClinicalTrials.gov

Clinical data

Trade names	Ekterly
Other names	KVD-900, KVD900
License data	US DailyMed: Sebetralstat
Routes of administration	By mouth
ATC code	B06AC08 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1933514-13-6
PubChem CID	121365142
IUPHAR/BPS	11947
DrugBank	DB18305
ChemSpider	115006749
UNII	O5ZD2TU2B7
KEGG	D12396
ChEMBL	ChEMBL5095248
Chemical and physical data
Formula	C₂₆H₂₆FN₅O₄
Molar mass	491.523 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

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