Progerinin

CAS 2249696-72-6

MF C23H22O4 MW 362.42

(3S)-2,2-dimethyl-3-[(E)-3-phenylprop-2-enoxy]-3,4-dihydropyrano[3,2-g]chromen-8-one

(7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one

(7S)-7,8-Dihydro-8,8-dimethyl-7-[[(2E)-3-phenyl-2-propen-1-yl]oxy]-2H,6H-benzo[1,2-b:5,4-b?]dipyran-2-one

(7S)-8,8-dimethyl-7-{[(2E)-3-phenylprop-2-en-1-yl]oxy}-7,8-dihydro-2H,6H-benzo[1,2-b:5,4-b’]dipyran-2-one
progerin-lamin A binding inhibitor, SLC-D011, SLC D011, KC 3, 426P9HSR8I

Progerinin (SLC-D011) is an orally active, targeted inhibitor designed to reduce the toxic, premature-aging protein “progerin” in Hutchinson-Gilford Progeria Syndrome (HGPS). It binds to progerin, disrupting its interaction with lamin A and promoting its degradation. Studies show it improves cardiac function, increases lifespan in mouse models, and is currently in clinical trials

Key Aspects of Progerinin:

• Mechanism of Action: Progerinin is an optimized progerin-lamin A binding inhibitor that selectively reduces progerin levels while sparing wild-type lamin A, B, and C.
• Disease Application: It targets HGPS, a rare genetic disease that causes premature, rapid aging and death due to cardiac issues.
• Preclinical Results: In Lmna mouse models, progerinin demonstrated improved physical conditions (hair morphology, body weight) and significantly extended lifespan (up to 14–21 weeks).
• Cardiac Benefits: It alleviates cardiovascular abnormalities, such as reducing cardiac muscle weakness, which is a major cause of death in HGPS patients.
• Clinical Status: A Phase I clinical trial was conducted for safety in healthy volunteers. As of 2025, trials are examining its efficacy, sometimes in combination with lonafarnib (Zokinvy).
• Administration: It is developed as a nanosuspension for oral administration. National Institutes of Health (NIH) | (.gov) +7

Progerinin was developed by Korean-based biotech company PRG Science & Technology Co., Ltd. (PRG S&T)

Progerinin (SLC-D011) is an orally active progerin-lamin A binding inhibitor. Progerinin selectively binds to the C-terminal region of progerin, disrupting its interaction with lamin A and promoting progerin degradation while sparing wild-type lamin A, B, and C. Progerinin ameliorates nuclear deformation, increases H3K9me3 levels, and reduces progerin expression in HGPS patient-derived fibroblasts. Progerinin extends lifespan in Lmna^G609G/G609G mice and Lmna^G609G/+ mice, improves body weight, hair morphology, cardiac function, and histological phenotypes. Progerinin can be used for the study of Hutchinson-Gilford progeria syndrome (HGPS).

• Study to Determine Optimal Dose and Evaluate Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients With Hutchinson-Gilford Progeria Syndrome (HGPS)CTID: NCT06775041Phase: Phase 2Status: Active, not recruitingDate: 2026-02-09
• Phase 2, Open-Label Study to Evaluate the Safety and Tolerability of Progerinin in Werner SyndromeCTID: NCT05847179Phase: Phase 2Status: Not yet recruitingDate: 2026-01-23
• Phase I Study of Progerinin in Healthy VolunteersCTID: NCT04512963Phase: Phase 1Status: CompletedDate: 2021-09-22

PAPER

Synthesis of (S)-(+)-decursin and its analogues as potent inhibitors of melanin formation in B16 murine melanoma cells

Publication Name: European Journal of Medicinal Chemistry

Publication Date: 2010-12

PMID: 20884093

DOI: 10.1016/j.ejmech.2010.09.006

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US283323867&_cid=P11-MMEAST-24660-1

<Example 1> Synthesis of Ether-Form (+)-Decursin Derivative (SLC-D011)

(7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one (SLC-D011) was synthesized through the manner as in the to following Reaction Schemes 1 and 2.

1. Synthesis Process I

Step (I): After dissolving trans-cinnamic acid (D0111a, 5 g, 33.7 mmol) in methanol (50 ml) in a 100 ml round bottom flask, 5 drops of concentrated H 2SO 4 was added and the mixture was refluxed by heating at 80° C. for 24 hours and was cooled to room temperature and then concentrated under reduced pressure.

Then, the mixture was separated with dichloromethane (300 ml) and distilled water (300 ml) to collect the organic layer and dehydrated with sodium sulfate and filtered.

After filtration, the filtrate was concentrated under reduced pressure to obtain 3-phenyl-acrylic acid, methyl ester (D011b, 5.39 g, yield=98.5%) as a pure product to apply to the next step.

Step (II): 3-phenyl-acrylic acid, methyl ester (D011b, 4 g, 24.7 mmol, 1 eq) was added into a 500 ml round bottom flask filled with N 2 gas and was dissolved in anhydrous dichloromethane and then placed in a low-temperature reactor set at −78° C.

Diisobutylaluminium hydride 1M solution (DIBAL-H; 1M solution in hexane, 74 ml, 74.0 mmol, 3 eq) was slowly added dropwise over 30 minutes to the reaction solution and methanol (22 ml) was slowly added dropwise while the reaction temperature was raised to 0° C. and stirring was carried out for 1 hour.

The reaction solution was transferred to room temperature, stirred for 30 minutes and then a saturated aqueous solution of Rochelle’s salt (88 ml) was added thereto.

The reaction mixture was vigorously stirred at room temperature for 2 hours, and the mixture was partitioned twice with dichloromethane (300 ml) and distilled water (300 ml) to collect the organic layers and was dehydrated with sodium sulfate, filtered and the resulting filtrate was concentrated under reduced pressure.

The concentrate was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:1) to obtain the pure product 3-phenyl-pro-2-pen-1-ol (D011c, 3.1 g, yield=93.9%, Rf=0.37 (2:1 n-hexane-ethyl acetate) to apply to the next step.

Step (III): To a 100 ml round bottom flask was added 3-phenyl-pro-2-pen-1-ol (D011c, 1 g, 7.45 mmol, 1 eq), was dissolved in anhydrous dichloromethane, PBr 3 (phosphoric tribromide, 253.6 μl, 2.608 mmol, 0.35 eq) was added on the steam bath and stirred for 1 hour.

The reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8) to obtain the pure product, 3-bromo-propenyl)-benzene (D005d, 1.42 g, yield=96.2%, Rf=0.34 (5:1 n-hexane-ethyl acetate) which was applied to the next step.

Step (IV): (S)-(+)-decursinol (SLC-B001, 2.33 g, 9.47 mmol, 1 eq) was dissolved in anhydrous N,N-dimethylformamide (DMF, 10 ml) in a 100 ml round bottom flask under an N 2 gas and was placed in a low temperature reactor set at −20° C.

(3-bromo-propenyl)-benzene (D005d, 2.8 g, 14.2 mmol, 1.5 eq) and sodium sulfate (NaH 60%, 757 mg, 18.9 mmol) were added to the reaction mixture and stirred for 4 hours. 3 ml of distilled water was added and after 10 minutes, it was taken out from the low-temperature reactor. Then, it was separated into twice with dichloromethane (200 ml) and distilled water (200 ml) to collect the organic layer and dehydrated with sodium sulfate, filtered and the resulting filtrate was concentrated under reduced pressure.

The concentrate was separated by silica gel column chromatography (ethyl acetate:n-hexane=gradient elution to 1:3 from 1:10) to obtain (7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one (SLC-D011) of 1.21 g, (35.3%). Yield 35.3%, white solid, mp: 143° C., R f=0.39 (2:1 n-hexane-ethyl acetate); [α] 25 D+117.6 (c=1, CHCl 3); 1H NMR (400 MHz, CDCl 3): δ H 7.56 (1H, d, J=9.6 Hz, H-4), 7.38-7.23 (5H, m, H-5′, H-6′, H-7′, H-8′, H-9′), 7.15 (1H, s, H-5), 6.76 (1H, s, H-10), 6.59 (1H, d, J=16.0 Hz, H-3′), 6.30-6.23 (1H, m, H-2′), 6.20 (1H, d, J=9.6 Hz, H-3), 4.34 (1H, dd, J=6.0, 12.8 Hz, H-1a′), 4.21 (1H, dd, J=6.0, 12.4 Hz, H-1b′), 3.59 (1H, dd, J=5.2, 7.6 Hz, H-7), 3.07 (1H, dd, J=4.8, 16.0 Hz, H-6a), 2.85 (1H, dd, J=7.2, 16.4 Hz, H-6b), 1.41 (3H, s CH 3-8), 1.36 (3H, s, CH 3−8); 13C NMR (100 MHz, acetone-d 6) δ C 161.2 (C-2), 157.8 (C-9a), 155.3 (C-10a), 144.5 (C-4), 137.9 (C-4′), 132.9 (C-3′), 130.4 (C-5), 129.6 (C-6′, C-8′), 128.6 (C-7′), 127.5 (C-2′), 127.4 (C-5′, C-9′), 118.3 (C-5a), 113.7 (C-3), 113.6 (C-4a), 104.5 (C-10), 78.8 (C-7), 76.4 (C-8), 70.8 (C-1′), 27.8 (C-6), 26.1 (CH 3-8), 22.2 (CH 3-8); ESI-MS: m/z=363 [M+H] +. Anal. Calc. for C 23H 22O 4: C, 76.22; H, 6.12; Found: C, 76.20; H, 6.10.

2. Synthesis Process II

Step (I): After dissolving trans-cinnamic acid (D011a, 5 g, 33.7 mmol) in methanol (50 ml) in a 100 ml round bottom flask, 5 drops of concentrated H 2SO 4 was added and the mixture was refluxed by heating at 80° C. for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure and was separated with dichloromethane (300 ml) and distilled water (300 ml) to collect the organic layer and dehydrated with sodium sulfate and filtered.

After filtration, the obtained filtrate was concentrated under reduced pressure to obtain 3-phenyl-acrylic acid, methyl ester (D011b, 5.39 g, yield=98.5%) as a pure product which was applied to the next step.

Step (II): 3-phenyl-acrylic acid, methyl ester (D011b, 4 g, 24.7 mmol, 1 eq) was added into a 500 ml round bottom flask filled with N 2 gas and was dissolved in anhydrous dissolved in anhydrous dichloromethane and then placed in a low-temperature reactor set at −78° C.

Diisobutylaluminium hydride 1M solution (DIBAL-H; 1M solution in hexane, 74 ml, 74.0 mmol, 3 eq) was slowly added dropwise over 30 minutes to the reaction solution and methanol (22 ml) was slowly added dropwise while the reaction temperature was raised to 0° C. and stirring was carried out for 1 hour.

The reaction solution was transferred to room temperature, stirred for 30 minutes and then a saturated aqueous solution of Rochelle’s salt (88 ml) was added thereto. The reaction mixture was vigorously stirred at room temperature for 2 hours, and the mixture was partitioned twice with dichloromethane (300 ml) and distilled water (300 ml).

The organic layers were collected and were dehydrated with sodium sulfate, filtered and the resulting filtrate was concentrated under reduced pressure.

The concentrate was separated by silica gel column chromatography (ethyl acetate:n-hexane=3:1) to obtain the pure product 3-phenyl-pro-2-pen-1-ol (D011c, 3.1 g, yield=93.9%, Rf=0.37 (2:1 n-hexane-ethyl acetate) which was applied to the next step.

Step (III): 3-phenyl-prop-2-pen-1-ol (D011c, 1 g, 7.45 mmol, 1 eq) was added to a 100 ml round bottom flask filled with N 2 gas and was dissolved in anhydrous dichloromethane, and trimethylamine (Et 3N, 1.04 ml, 7.45 mmol, 1 eq), 4-dimethylaminopyridine (4-DMAP, 92 mg, 0.75 mmol, 0.1 eq), di-tert-butyl-dicarbonate (0.13 ml, 7.45 mmol, 1 eq), 4-dimethylaminopyridine (4-DMAP, 92 mg, 0.75 mmol, tert-butyl-dicarbonate (Boc2O, 2.57 ml, 11.18 mmol, 1.5 eq) were sequentially added, and the reaction solution was stirred at room temperature for 2 hours.

The reaction mixture was concentrated and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30) to obtain the pure product, tert-butyl cinnamyl carbonate (D011d, 1.30 g, yield=74.7%, Rf=0.32 (20:1 n-hexane-ethyl acetate)) which was applied to the next step.

Step (IV): Tert-butyl cinnamyl carbonate (D011d, 1.43 g, 6.09 mmol, 1.5 eq), (S)-(+)-decursinol (SLC—4.06 mmol, 1 eq) were added into a 100 ml round bottom flask and the mixture was dried under vacuum for 1 hour.

The dried mixture was dissolved in anhydrous tetrahydrofuran under N 2 gas and after bubbling the solution for 1 hour using N 2 gas, tetrakis(triphenylphosphine) palladium (Pd (PPh 3) 4, 188 mg, 0.162 mmol, 0.04 eq) was added to the reaction mixture and was refluxed overnight. The mixture liquid was concentrated under reduced pressure, and was separated by silica gel column chromatography (ethyl acetate:n-hexane=gradient elution to 1:4 from 1:8) to obtain compound (7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one (SLC-D011) of 1.20 g (81.3%). Yield 81.3%, white solid, mp: 143° C., R f=0.39 (2:1 n-hexane-ethyl acetate); [α] 25 D+117.6 (c=1, CHCl 3); 1H NMR (400 MHz, CDCl 3): δ H 7.56 (1H, d, J=9.6 Hz, H-4), 7.38-7.23 (5H, m, H-5′, H-6′, H-7′, H-8′, H-9′), 7.15 (1H, s, H-5), 6.76 (1H, s, H-10), 6.59 (1H, d, J=16.0 Hz, H-3′), 6.30-6.23 (1H, m, H-2′), 6.20 (1H, d, J=9.6 Hz, H-3), 4.34 (1H, dd, J=6.0, 12.8 Hz, H-1a′), 4.21 (1H, dd, J=6.0, 12.4 Hz, H-1b′), 3.59 (1H, dd, J=5.2, 7.6 Hz, H-7), 3.07 (1H, dd, J=4.8, 16.0 Hz, H-6a), 2.85 (1H, dd, J=7.2, 16.4 Hz, H-6b), 1.41 (3H, s CH 3-8), 1.36 (3H, s, CH 3-8); 13C NMR (100 MHz, acetone-d 6) δ C 161.2 (C-2), 157.8 (C-9a), 155.3 (C-10a), 144.5 (C-4), 137.9 (C-4′), 132.9 (C-3′), 130.4 (C-5), 129.6 (C-6′, C-8′), 128.6 (C-7′), 127.5 (C-2′), 127.4 (C-5′, C-9′), 118.3 (C-5a), 113.7 (C-3), 113.6 (C-4a), 104.5 (C-10), 78.8 (C-7), 76.4 (C-8), 70.8 (C-1′), 27.8 (C-6), 26.1 (CH 3-8), 22.2 (CH 3-8); ESI-MS: m/z=363 [M+H]+. Anal. Calc. for C 23H 22O 4: C, 76.22; H, 6.12; Found: C, 76.20; H, 6.10.

PAT

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• Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredientPublication Number: CN-110573514-APriority Date: 2017-04-25
• Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredientPublication Number: US-11008332-B2Priority Date: 2017-04-25Grant Date: 2021-05-18
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//////////progerinin, progerin-lamin A binding inhibitor, SLC-D011, SLC D011, KC 3, 426P9HSR8I