MK 0893 |
| Catalog No.GC14793 |
MK 0893은 강력하고 선택적인 혈당 상승 호르몬 수용체(GCGR) 앙티아고니스트로, IC50 값이 6.6 nM이다.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 870823-12-4
Sample solution is provided at 25 µL, 10mM.
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MK 0893은 강력하고 선택적인 혈당 상승 호르몬 수용체(GCGR) 앙티아고니스트로, IC50 값이 6.6 nM이다.
MK 0893의 작용 메커니즘은 G 단백질 신호 전달에 필요한 transmembrane helix 6 (TM6) 단백질의 움직임을 제한하여CGR 성을 방지하는 것이다[2]. MK-0893은 2형 당뇨병 환자를 치료하고 식후 혈당을 효과적으로 낮추지만, 간 아미노기 전환효소 수치가 증가시켜 임상 개발에 적합하지 않는다[3].
체외 실험에서 MK 0893(0-1000nM)은 인간 원주성 간세포에 1시간 동안 처리되어 혈당 상승 호르몬의 작용을 억제하고 cAMP의 생성을 유도하는 것을 방지하며, IC50 값이 563nM으로 나타났다[4]. MK 0893(0-400nM)은 INS-1 832/13 세포에 처리되어 혈당 상승 호르몬의 작용을 억제하고 또한 혈당 상승 호르몬 유사peptide-1 (GLP-1)의 작용을 억제하였다[5].
체내 실험에서 hGCGR ob/ob 쥐에게 MK 0893(3, 10 mg/kg)을 구강 투여하여 각각 3mg/kg 및 10mg/kg 단일 용량으로 혈당 수준을 32%와 39% 감소시켰다[1]. WT와 hGCGR 쥐에게 구강으로 MK 0893(3, 10 mg/kg)을 투여한 결과 WT 쥐의 혈장 콜레스테롤이나 식물 스테롤 수준에 유의미한 영향을 미치지 않았지만, 10 mg/kg 용량에서 채소스테롤 수준을 현저하게 증가시켰다. hGCGR 쥐에서 MK 0893은 혈장의 시토스테롤 수준에서 용량에 따라 증가하는 경향을 보였다[4].
References:
[1] Xiong Y, Guo J, Candelore M R, et al. Discovery of a Novel Glucagon Receptor AntagonistN-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1 H-pyrazol-1-yl] ethyl} phenyl) carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes[J]. Journal of medicinal chemistry, 2012, 55(13): 6137-6148.
[2] Crunkhorn S. Glucagon receptor antagonist binding site identified[J]. Nature Reviews Drug Discovery, 2016, 15(6): 384-384.
[3] Christensen M, Bagger J I, Vilsboll T, et al. The alpha-cell as target for type 2 diabetes therapy[J]. The review of diabetic studies: RDS, 2011, 8(3): 369.
[4] Guan H P, Yang X, Lu K, et al. Glucagon receptor antagonism induces increased cholesterol absorption [S][J]. Journal of lipid research, 2015, 56(11): 2183-2195.
[5] Chepurny O G, Matsoukas M T, Liapakis G, et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP[J]. Journal of Biological Chemistry, 2019, 294(10): 3514-3531.
세포 실험 [1]: | |
세포 라인 | 인간의 일차 간세포 |
제조 방법 | 각 웰에 4000개의 세포가 MK-0893, GRA1 및 GRA2(0-1000nM)과 함께 30분 전 처리된 후, 방온에서 5nM의 글루카곤으로 30분 더 자극되었다. |
반응 조건 | 0-1000nM; 1 h |
응용 분야 | 글루카곤이 존재하는 상황에서 MK-0893, GRA1, 그리고 GRA2는 모두 cAMP 생성을 억제하며, 각각의 IC50가 563, 448, 292nM이다. |
동물 실험 [2]: | |
동물 모형 | hGCGR ob/ob 쥐 |
제조 방법 | MK 0893(3, 10mg/kg)를 구강으로 투여한 후 1시간째 hGCGR 유전자 nockout ob/ob 쥐에게, PBS에서 용해된 글루카곤(15μg/kg)을 복강 주사로 주입한 후, 꼬리 출혈을 통한 혈당 측정을 위해 혈당 측정기를 사용하였다. |
제형 | 3, 10mg/kg; p.o. |
응용 분야 | MK 0893은 10 mg/kg 및 3 mg/kg의 구강 투여량으로 각각 혈당 수준을 39%, 32% 감소시켰다. |
참고문헌: [1] Guan H P, Yang X, Lu K등. 혈당 호르몬 수용체 촉진작용은 콜레스테롤 흡수 증가를 유도한다[S][J]. 지질 연구 저널, 2015, 56(11): 2183-2195. [2] Xiong Y, Guo J, Candelore M R, 등. 2형 당뇨병 치료를 위한 새로운 혈당 호르몬 수용체 촉진작용제 N-[(4-{(1)-1-[--5 (3, 5-Dichlorophenyl)-3-1 (6-methoxynaphthalen-2-yl) H-pyrazol-1-yl]에 틸}페닐)카본릴]-β-알라닌 (MK-0893)의 발견[J]. 의학 화학 저널, 2012, 55(13): 6137-6148. | |
| Cas No. | 870823-12-4 | SDF | |
| Chemical Name | 3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid | ||
| Canonical SMILES | CC(C1=CC=C(C=C1)C(=O)NCCC(=O)O)N2C(=CC(=N2)C3=CC(=CC(=C3)Cl)Cl)C4=CC5=C(C=C4)C=C(C=C5)OC | ||
| Formula | C32H27Cl2N3O4 | M.Wt | 588.48 |
| Solubility | ≥ 24.05 mg/mL in DMSO, ≥ 4.8 mg/mL in EtOH with ultrasonic and warming | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 1.6993 mL | 8.4965 mL | 16.9929 mL |
| 5 mM | 339.9 μL | 1.6993 mL | 3.3986 mL |
| 10 mM | 169.9 μL | 849.6 μL | 1.6993 mL |
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