WO2022240036A1 - 섬유화증의 예방 또는 치료용 약학적 조성물 - Google Patents
섬유화증의 예방 또는 치료용 약학적 조성물 Download PDFInfo
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Definitions
- the first component contains 100 to 150 mg.
- the content of the second component may be adjusted according to the content of the first component.
- the second component is the compound represented by Formula 2, or a pharmaceutically acceptable salt thereof, and contains 100 to 150 mg of the first component, Contains 200 to 800 mg of 2 components.
- examples of the fibrosis include interstitial lung disease (ILD), scleroderma, keloid, hypertrophic scar, non-alcoholic fatty liver (Non-alcoholic Fatty Liver Disease), Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, age-related macular degeneration (AMD), hypertrophic cardiomyopathy , myocardial infarction, muscular dystrophy, diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or inflammatory bowel disease (IBD) have.
- IBD interstitial lung disease
- scleroderma keloid
- hypertrophic scar non-alcoholic fatty liver (Non-alcoholic Fatty Liver Disease)
- PSC Primary sclerosing cholangitis
- PBC primary biliary cholangitis
- AMD age-related macular degeneration
- hypertrophic cardiomyopathy myocardial infarction
- muscular dystrophy diabetic kidney
- the interstitial lung disease includes idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or progressive chronic fibrosing interstitial lung diseases with a progressive phenotype, PF-ILD).
- IPF idiopathic pulmonary fibrosis
- SSc-ILD systemic sclerosis associated interstitial lung disease
- PF-ILD progressive chronic fibrosing interstitial lung diseases with a progressive phenotype
- compositions of the present invention may be formulated for oral or parenteral administration according to standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carriers, adjuvants, or diluents in addition to active ingredients.
- Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate, and diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or or glycine, but is not limited thereto.
- the compounds of the present invention can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions.
- the compounds of the present invention may be formulated as ointments or creams.
- the compounds of the present invention are formulated as injections by dissolving, suspending or emulsifying the compounds in aqueous solvents such as saline, 5% dextrose or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol. It can be.
- aqueous solvents such as saline, 5% dextrose or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol. It can be.
- the formulation of the present invention may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
- a preferred dose of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, it is recommended to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight) per day, preferably 0.001 to 100 mg/kg (body weight). Administration can be administered via an oral or parenteral route once a day or in divided doses. Depending on the method of administration, the composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound of the present invention.
- Figure 4 shows the histopathological analysis results of Experimental Examples 2-3 of the present invention.
- NIN Nintedanib
- PID pirfenidone
- 10 mM of the first component was diluted in DMSO to 100 uM. It was diluted to 10, 3, and 1 uM by dilution with DMSO, and diluted to 50 nM by dilution of 10 mM of the second component (NIN) with DMSO.
- a lung fibrosis cell line, DHLF cell line (FGMTM-2 Bullet Kit TM, 10% FBS) was prepared and cultured in a T75 Easy Flask Filter using FBM medium at 37°C and 5% CO 2 conditions.
- the cultured DHLF cell line was treated with TGF- ⁇ 10 ng/mL and test drugs alone or in combination, and after 72 hours of culture, the media was removed, and proteins were extracted, and the extracted proteins were quantified using the BCA Protein Assay Kit. Based on the quantitative value of each extracted protein, 10 ⁇ 20 ug of protein was Western Blotted.
- each PVDF membrane was treated with 1 mL of ECL solution, and the protein expression level was measured using an AI680 imager.
- Each band value is shown in Tables 2 and 3 and FIGS. 1 and 2 below by calculating normalized numerical values compared to ⁇ -actin through ImageJ.
- TGF- ⁇ Second Component (NIN) first component No. relative value (based on control) COL1A1 SMA- ⁇ - - control 4 1.00 1.00 10 ng/mL vehicle 4 6.25 3.78 50 ng/mL - 4 4.60 2.63 1 ⁇ g/ml 4 4.31 2.40 3ug/ml 4 3.09 1.56 10ug/ml 4 2.14 1.05 - 10ug/ml 4 3.26 1.66
- TGF- ⁇ 1st ingredient Second Component No. relative value (based on control) COL1A1 SMA- ⁇ - control - 2 1.00 1.00 10 ng/mL vehicle - 2 4.83 6.73 5ug/ml - 2 3.84 3.53 25 ng/mL 2 4.11 3.58 50 ng/mL 2 3.12 2.10 100 ng/mL 2 1.81 0.77 - 100 ng/mL 2 2.81 2.99
- BLM solution bleomycin 1 ⁇ 3 mg/kg
- test drug was administered and BLM administration 21
- the drug was administered orally for 2 weeks until the day.
- the composition of the experimental group is shown in Table 4 below, and the anti-fibrotic efficacy was measured by measuring body weight, SpO2, hydroxyproline and inflammation cell count.
- Normal vehicle first component (10 mg/kg) Second Component (NIN) (60 mg/kg) 1st component (10 mg/kg) + 2nd component (NIN) (60 mg/kg) Second component (PID) (200 mg/kg) 1st component (10 mg/kg) + 2nd component (PID) (200 mg/kg) medium 99.0 76.0 79.1 79.8 82.2 81.7 85.1 difference 0.0 3.1 3.8 6.2 5.7 9.1 rate of increase 0% 4% 5% 8% 7% 12%
- the oxygen permeation function of the lungs was confirmed by measuring mouse abdominal SpO2, and it was confirmed that it was improved by more than 50% when administered in combination (PID and the first component, 12%) than when administered alone (PID, 7%). This is a result confirming that the direct improvement effect of lung function is increased when co-administered through an increase in oxygen permeability, which is reduced in the process of pulmonary fibrosis.
- Lung fibrosis is the accumulation of collagen in the lungs and hardening, and the main cause of such lung fibrosis is the accumulation of collagen, and the degree of fibrosis progress can be predicted by measuring the collagen content in the lung tissue.
- the degree of fibrosis and inflammation of the lung tissue was visually observed through a microscope, and the degree of fibrosis of the lung tissue was measured by the Fibrotic Index according to the normalized standard. The higher the Fibrotic Index value, the more severe the degree of fibrosis and the disease, and the lower the value, the less severe the disease.
- Body weight is an indirect indicator of the degree of improvement in the overall body condition of the animal model, and when the degree of weight loss is small, it can be assumed that the overall body condition or symptoms of the disease are improved.
- Body weight was measured once every 0, 7, 14, 17, and 21 days for 3 weeks, and it was measured every 3 days from the 14th day when the drug effect began to be noticeable after administration. The results are shown in Table 9 and FIG. 8 below.
- Microcrystalline cellulose, lactose hydrate, crospovidone, and magnesium stearate were mixed with the hydrochloride form of the first component to prepare a compressed plate using a dry granulator, and pulverized with an oscillator to prepare dry granules.
- Microcrystalline cellulose, lactose hydrate, and magnesium stearate were additionally mixed with the granules, and compression molding was performed to prepare a tablet, which was completed by proceeding with enteric coating.
- the maximum plasma concentration was recorded within 1.5 hours to 8 hours after administration, the geometric mean half-life ranged from 6.91 hours to 9.90 hours, and the plasma concentration was confirmed to increase in a dose proportional relationship.
- the maximum plasma concentration was recorded within 1.5 to 5 hours in a steady state after administration, and the geometric mean half-life ranged from 4.4 hours to 12.35 time range, and the geometric mean dose interval period in vivo exposure (AUC ⁇ ) was in the range of 183.32-3012.35 h ⁇ ng/mL. It was confirmed that the plasma concentration was in a dose-linear relationship within the dose range of 25 mg to 200 mg of the active ingredient.
- Subjects enrolled in Part 1 were sequentially administered with a single dose of 600 mg of the second component (PID) in phase 1, a single administration of 150 mg of the first component in phase 2, followed by a 3-day washout, and multiple administrations of 150 mg of the first component for 3 days.
- the first component and the second component (PID) were administered in combination
- the subjects enrolled in Part 2 were administered with a single dose of the second component (NIN) 150 mg in the first period, and the first component 150 mg 3 days in the second period.
- the first component and the second component (NIN) were administered in combination once in the last 3 periods.
- the target group is divided into patients receiving pirfenidone as an existing standard treatment, patients receiving nintedanib, and patients not receiving any treatment. to confirm the effect of combined administration with standard treatment compared to single administration. If an adverse reaction occurs due to the first component, closely monitor the patient's reaction and reduce the dose.
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Abstract
Description
Function | Control(or reference) Article | Control(or reference) Article |
Compound Name | Nintedanib | Pirfenidone |
Salt form | Free | Free |
Manufacturer | U chem | Combi-Blocks |
Supplier | U chem | Combi-Blocks |
TGF-β | 제2 성분(NIN) | 제1 성분 | No. | 상대값 (control 기준) |
|
COL1A1 | SMA-α | ||||
- | - | control | 4 | 1.00 | 1.00 |
10 ng/ml | vehicle | 4 | 6.25 | 3.78 | |
50 ng/ml | - | 4 | 4.60 | 2.63 | |
1 ug/ml | 4 | 4.31 | 2.40 | ||
3 ug/ml | 4 | 3.09 | 1.56 | ||
10 ug/ml | 4 | 2.14 | 1.05 | ||
- | 10 ug/ml | 4 | 3.26 | 1.66 |
TGF-β | 제1성분 | 제2 성분(NIN) | No. | 상대값 (control 기준) |
|
COL1A1 | SMA-α | ||||
- | control | - | 2 | 1.00 | 1.00 |
10 ng/ml | vehicle | - | 2 | 4.83 | 6.73 |
5 ug/ml | - | 2 | 3.84 | 3.53 | |
25 ng/ml | 2 | 4.11 | 3.58 | ||
50 ng/ml | 2 | 3.12 | 2.10 | ||
100 ng/ml | 2 | 1.81 | 0.77 | ||
- | 100 ng/ml | 2 | 2.81 | 2.99 |
Group | Article | No of Animals (Male) | Dose 1 | Dose 2 | Volume | Route of administration |
(mg/kg) | (mg/kg) (SoC) | (uL) | ||||
G1(NC) | Saline | 9 | N/A | N/A | 100 | PO |
G2(PC) | Saline | 9 | N/A | N/A | 100 | PO |
G3(Test) | 제1 성분 | 9 | 10 | N/A | 100 | PO |
G4(Test) | 제2 성분(NIN) | 9 | N/A | 60 | 100 | PO |
G5(Test) | 제2 성분(PID) | 9 | N/A | 200 | 100 | PO |
G6(Test) | 제1 성분+제2 성분(NIN) | 9 | 10 | 60 | 100 | PO |
G7(Test) | 제1 성분+제2 성분(PID) | 9 | 10 | 200 | 100 | PO |
Normal | vehicle | 제1 성분 (10 mg/kg) |
제2 성분(NIN) (60 mg/kg) |
제1 성분(10 mg/kg) + 제2 성분(NIN)(60 mg/kg) | 제2 성분(PID)(200 mg/kg) | 제1 성분(10 mg/kg) + 제2 성분(PID)(200 mg/kg) | |
평균값 | 99.0 | 76.0 | 79.1 | 79.8 | 82.2 | 81.7 | 85.1 |
차이 | 0.0 | 3.1 | 3.8 | 6.2 | 5.7 | 9.1 | |
증가율 | 0% | 4% | 5% | 8% | 7% | 12% |
Day/n | PBS | BLM | 제1 성분 (10 mg/kg) |
제2 성분(NIN) (60 mg/kg) |
제2 성분(PID) (200 mg/kg) |
제1 성분 (10 mg/kg) + 제2 성분(NIN)(60 mg/kg) |
제1 성분 (10 mg/kg) + 제2 성분(PID)(200 mg/kg) |
21/9 | 88 | 246 | 228 | 192 | 156 | 183 | 120 |
그룹 | 개체수 | Fibrotic Index (±SEM) |
Normal | 9 | 0.5 (±0.4) |
vehicle | 9 | 5.5 (±0.6) |
제1 성분(10 mg/kg) | 9 | 4.6 (±0.6) |
제2 성분(PID)(200 mg/kg) | 9 | 3.7 (±0.7) |
제1 성분(10 mg/kg) + 제2 성분(PID)(200 mg/kg) | 9 | 1.9 (±0.5) |
Group | n | Macrophage | Eosinophil | Neutrophil | Lymphocyte | total cell (10^4) |
PBS | 9 | 3 | 0 | 0 | 0 | 3 |
BLM | 9 | 66 | 0 | 22 | 11 | 98 |
제1 성분 (10 mg/kg) |
9 | 60 | 0 | 17 | 7 | 84 |
제2 성분(NIN) (60 mg/kg) |
9 | 53 | 0 | 10 | 5 | 69 |
제1 성분 (10 mg/kg) + 제2 성분(NIN)(60 mg/kg) |
9 | 30 | 0 | 6 | 3 | 39 |
제2 성분(PID) (200 mg/kg) |
9 | 55 | 0 | 12 | 6 | 74 |
제1 성분 (10 mg/kg) + 제2 성분(PID)(200 mg/kg) |
9 | 38 | 0 | 8 | 4 | 50 |
Day/n | PBS | BLM | 제1 성분 (10 mg/kg) |
제2 성분 (NIN) (60 mg/kg) |
제2 성분 (PID) (200 mg/kg) |
제1 성분 (10 mg/kg) + 제2 성분 (NIN)(60 mg/kg) |
제1 성분 (10 mg/kg) + 제2 성분 (PID)(200 mg/kg) |
0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
7 | 3.2 | -10.1 | -10.1 | -10.1 | -10.2 | -12.1 | -13.0 |
14 | 6.1 | -22.5 | -22.7 | -22.6 | -22.7 | -23.8 | -18.7 |
17 | 9.3 | -24.8 | -22.2 | -20.0 | -18.1 | -21.5 | -17.1 |
21 | 13.3 | -23.0 | -20.5 | -18.2 | -16.5 | -16.0 | -12.2 |
실험동물 | ICR mice (male) |
투여 경로 | 경구 |
투여 횟수 | 단회 |
투여 용량(mg/kg) | 10 |
투여 액량(mL/kg) | 10 |
채혈 시간 (hr) | 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 |
부형제 | saline |
시험동물 수 | 6 (n=3, 교차채혈) |
시험물질 | 제1성분 |
투여 용량(mg/kg) | 10 |
t1/2 (hr) | 2.50 ± 2.48 |
Tmax (hr) | 2.67 ± 1.15 |
Cmax (μg/mL) | 0.263 ± 0.032 |
AUC0-t (hr·μg/mL) | 1.07 ± 0.21 |
AUCinf (hr·ng/mL) | 1190 |
구분 | 그룹 | 활성 성분 | 제형 | 투여 방법 |
단회투여 | SAD1 | 100 mg | 장용코팅캡슐 | 공복 상태에서 단회 경구 투여 |
SAD2 | 300 mg | |||
SAD3 | 600 mg | |||
SAD4 | 500 mg | 장용코팅정제 | ||
다회투여 | MAD1 | 25 mg | 13일 연속 1일 2회 공복 상태에서 경구 투여 후 14일째 아침 단회 투여 | |
MAD2 | 50 mg | |||
MAD3 | 100 mg | |||
MAD4 | 200 mg |
항목(GCV%) | 활성 성분 100 mg (N=6) |
활성 성분 300 mg (N=6) |
활성 성분 600 mg (N=6) |
활성 성분 500 mg (N=6) |
Cmax (ng/mL) | 123.96 (37.72) | 276.80 (66.21) | 213.43 (433.75) | 513.56 (41.27) |
tmax (h)* | 3.00 (1.50, 4.00) | 2.50 (1.50, 8.00) | 2.00 (1.50, 5.00) | 3.01 (0.50, 5.00) |
AUC0-last (h*ng/mL) | 594.10 (61.23) | 1478.84 (48.07) | 1008.65 (625.00) | 2282.37 (54.92) |
AUC0-∞ (h*ng/mL) | 639.07 (58.10) | 1525.99 (47.06) | 1922.64 (222.08) | 2339.20 (53.27) |
T1/2 (h) | 6.91 (39.98) | 8.33 (24.57) | 9.90 (71.50) | 7.80 (13.49) |
Vz/F (L) | 1560.44 (34.98) | 2361.87 (41.96) | 4459.07 (84.14) | 2406.62 (48.04) |
CL/F (L/h) | 156.48 (58.10) | 196.59 (47.06) | 312.07 (222.08) | 213.75 (53.27) |
MRT (h) | 9.26 (33.69) | 9.75 (21.76) | 9.79 (25.60) | 9.57 (27.28) |
GCV% = Geometric coefficient of variation Notes: tmax represented as median; min, max. |
항목 (GCV%) | 활성 성분 25 mgT
(N=6) |
활성 성분 50 mgT
(N=6) |
활성 성분 100 mgT
(N=6) |
활성 성분 200 mgT
(N=6) |
Day 14 | ||||
Cmax, ss (ng/mL) | 36.50 (66.19) | 102.61 (67.99) | 151.27 (65.36) | 595.35 (36.32) |
tmax, ss (h)* | 2.00 (1.50, 4.00) | 3.00 (3.00, 5.00) | 3.00 (1.50, 4.00) | 2.00 (1.50, 5.00) |
AUCτ (h*ng/mL) | 183.32 (76.35) | 429.09 (128.63) | 617.40 (60.53) | 3012.35 (48.42) |
AUC0-∞ (h*ng/mL) | 300.73 (102.79) | 565.34 (232.53) | 887.97 (60.55) | 4747.29 (64.90) |
T1/2 (h) | 7.63 (46.84) | 4.40 (101.38) | 9.26 (22.69) | 12.35 (34.54) |
Vz/Fss (L) | 1433.79 (61.75) | 738.97 (34.90) | 2163.04 (63.58) | 1182.53 (48.47) |
CL/Fss (L/h) | 122.65 (79.49) | 116.53 (128.63) | 161.97 (60.53) | 66.39 (48.42) |
MRT (h) | 10.53 (31.65) | 8.44 (68.43) | 10.17 (9.35) | 12.07 (26.90) |
Accumulation ratio based on AUCτ | 1.94 (26.34) | 2.33 (31.42) | 1.88 (35.07) | 3.75 (36.01) |
Abbreviations: GCV% = Geometric coefficient of variation; n = Number of subjects; SD = Standard Deviation; T = Tablet. Notes: * tmax, ss represented as median; min, max. MRT, AUCτ, CL/Fss, and Vz/Fss are considering a 12 hour dosing interval. |
Dose (mg) | ||||
Parameter | 50 | 100 | 150 | 200 |
T1/2 (h) | 9.753195 | 9.753195 | 9.753195 | 9.753195 |
Tmax (h) | 2.803 | 2.803 | 2.803 | 2.803 |
Cmax (ng/mL) | 38.271 | 76.5419 | 114.813 | 153.084 |
CL/F (mL/hr) | 215856.7 | 215856.7 | 215856.7 | 215856.5 |
Vd/F (mL) | 3037295 | 3037295 | 3037295 | 3037293 |
AUCtau (hr*ng/mL) | 231.6352 | 463.2704 | 694.9055 | 926.5413 |
AUCtau_24hr (hr*ng/mL) | 463.2704 | 926.5407 | 1389.811 | 1853.08256 |
기존 투여 치료제 | 제1 성분 150 mg, BID | 제1 성분 100 mg, BID | 위약 (0 mg), BID |
피르페니돈 (mg, 1일3회 투여) | 801 | 801 | 801 |
534 | 534 | 534 | |
267 | 267 | 267 | |
600 | 600 | 600 | |
400 | 400 | 400 | |
200 | 200 | 200 | |
닌테다닙 (mg, 1일2회 투여) | 150 | 150 | 150 |
100 | 100 | 100 | |
어떠한 치료제도 투여하지 않음 (mg) | 0 | 0 | 0 |
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EP22807684.0A EP4338734A1 (en) | 2021-05-13 | 2022-05-02 | Pharmaceutical composition for prevention or treatment of fibrosis |
CA3213455A CA3213455A1 (en) | 2021-05-13 | 2022-05-02 | Pharmaceutical composition for preventing or treating fibrosis |
PE2023003019A PE20241171A1 (es) | 2021-05-13 | 2022-05-02 | Composicion farmaceutica para prevenir o tratar la fibrosis |
MX2023013405A MX2023013405A (es) | 2021-05-13 | 2022-05-02 | Composicion farmaceutica para prevenir o tratar la fibrosis. |
CN202280034620.XA CN117320718A (zh) | 2021-05-13 | 2022-05-02 | 用于预防或治疗纤维化的药物组合物 |
BR112023023670A BR112023023670A2 (pt) | 2021-05-13 | 2022-05-02 | Composição farmacêutica para prevenir ou tratar fibrose |
US18/288,275 US20240238278A1 (en) | 2021-05-13 | 2022-05-02 | Pharmaceutical Composition for Preventing or Treating Fibrosis |
JP2023567150A JP2024516021A (ja) | 2021-05-13 | 2022-05-02 | 線維化症の予防または治療用薬学的組成物 |
AU2022274469A AU2022274469A1 (en) | 2021-05-13 | 2022-05-02 | Pharmaceutical composition for prevention or treatment of fibrosis |
CONC2023/0015482A CO2023015482A2 (es) | 2021-05-13 | 2023-11-16 | Composición farmacéutica para prevenir o tratar la fibrosis |
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EP (1) | EP4338734A1 (ko) |
JP (1) | JP2024516021A (ko) |
KR (1) | KR20220154616A (ko) |
CN (1) | CN117320718A (ko) |
AR (2) | AR125885A1 (ko) |
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BR (1) | BR112023023670A2 (ko) |
CA (1) | CA3213455A1 (ko) |
CL (1) | CL2023003345A1 (ko) |
CO (1) | CO2023015482A2 (ko) |
EC (1) | ECSP23086047A (ko) |
MX (1) | MX2023013405A (ko) |
PE (1) | PE20241171A1 (ko) |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2010018134A1 (en) * | 2008-08-11 | 2010-02-18 | Smithkline Beecham Corporation | Novel adenine derivatives |
US20190282565A1 (en) * | 2018-03-19 | 2019-09-19 | Gui-Bai Liang | Methods and Compositions for Treating Idiopathic Pulmonary Fibrosis |
KR102084772B1 (ko) | 2017-02-07 | 2020-03-04 | 주식회사 대웅제약 | 신규한 헤테로 고리 화합물, 이의 제조 방법 및 이를 포함하는 약학적 조성물 |
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Patent Citations (3)
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WO2010018134A1 (en) * | 2008-08-11 | 2010-02-18 | Smithkline Beecham Corporation | Novel adenine derivatives |
KR102084772B1 (ko) | 2017-02-07 | 2020-03-04 | 주식회사 대웅제약 | 신규한 헤테로 고리 화합물, 이의 제조 방법 및 이를 포함하는 약학적 조성물 |
US20190282565A1 (en) * | 2018-03-19 | 2019-09-19 | Gui-Bai Liang | Methods and Compositions for Treating Idiopathic Pulmonary Fibrosis |
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LEE C.H., CHO M., KIM J.M., LEE J.H., KIM D.-W., PARK M.Y., KIM Y.K., HAN J., PARK J.S.: "A First-in-Class PRS Inhibitor, DWN12088, as a novel therapeutic agent for idiopathic pulmonary fibrosis", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 201, 1 January 2020 (2020-01-01), US , pages A2786, XP009541055, ISSN: 1073-449X * |
NAT. REV. CANCER, vol. 11, 2011, pages 708 - 718 |
NATURE, vol. 494, 2013, pages 121 - 125 |
SONG DAE-GEUN, KIM DOYEUN, JUNG JAE WOO, NAM SEO HEE, KIM JI EON, KIM HYE-JIN, KIM JONG HYUN, PAN CHEOL-HO, KIM SUNGHOON, LEE JUNG: "Glutamyl-Prolyl-tRNA Synthetase Regulates Epithelial Expression of Mesenchymal Markers and Extracellular Matrix Proteins: Implications for Idiopathic Pulmonary Fibrosis", FRONTIERS IN PHARMACOLOGY, vol. 9, no. 1337, pages 1 - 11, XP093004347, DOI: 10.3389/fphar.2018.01337 * |
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CL2023003345A1 (es) | 2024-06-07 |
CO2023015482A2 (es) | 2023-11-30 |
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US20240238278A1 (en) | 2024-07-18 |
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AU2022274469A1 (en) | 2023-09-21 |
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