MK-0974
(Synonyms: N-[(3R,6S)-6-(2,3-二氟苯基)六氢-2-氧代-1-(2,2,2-三氟乙基)-1H-氮杂卓-3-基]-4-(2,3-二氢-2-氧代-1H-咪唑并[4,5-B]吡啶-1-基)-1-哌啶甲酰胺,Telcagepant;MK0974;MK 0974) 目录号 : GC16478
A CGRP receptor antagonist
Cas No.:781649-09-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
MK-0974 (Telcagepant) is a highly potent, selective, and orally bioavailable antagonist of CGRP receptor with IC50 value of 0.77 nM [1].
Calcitonin gene-related peptide (CGRP) receptor is a heteromeric transmembrane receptor composed of a G protein-coupled receptor which is called calcitonin receptor-like receptor (CALCRL) and a receptor activity modifying protein 1 (RAMP1). CGRP receptor is functional for mediating the activity of CGRP, which is widely distributed in human peripheral and central neuron system. The CGRP/CGRP receptor signaling pathway modulate a variety of physiological functions of respiratory, immune and cardiovascular system, and play a key role in the pathophysiology of migraine headache.
When binding study was carried out, it was found MK-0974 had high affinity for CGRP receptor but had no affinity for related human adrenomedullin receptors, which suggested the high specificity of MK-0974 [1]. In human HEK293 cells expressing CGRP receptor, treatment of MK-0974 resulted in potent blockage of α-CGRP-stimulated cAMP producation, which indicated a significant inhibition of CGRP receptor activity. However, addition of 50% human serum reduced the inhibition potency of MK-0974 by 5-fold [1]. MK-0974 displayed reversible and saturable binding to both SK-N-MC membranes and rhesus cerebellum with a Kd of 1.9 nM and 1.3 nM, respectively [2].
In rhesus model, capsaicin-induced release of endogenous CGRP resulted in dermal vasodilation. Following treatment of MK-0974 produced a dose-dependent inhibition of dermal vasodilation, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. The suppression of CGRP function indicated the inhibition of CGRP receptor by MK-0974 [1]. In monkey model, MK-0974 showed moderate clearance (14-20 ml min-1 kg-1), while oral bioavailability was 6%. The pharmacokinetics of MK-0974 remained linear across 0.5-10 mg kg-1 intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) increase (5-30 mg kg-1) was 15-fold over dose-proportional [3].
References:
[1] Salvatore C A et al. , Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther. 2008, 324(2): 416-421.
[2] Moore E L et al. , Examining the binding properties of MK-0974: a CGRP receptor antagonist for the acute treatment of migraine. Eur J Pharmacol. 2009, 602(2-3): 250-254.
[3]. Roller S et al., Preclinical pharmacokinetics of MK-0974, an orally active calcitonin-gene related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences. Xenobiotica. 2009, 39(1): 33-45.
Cell experiment: | HEK293 cells stably transfected with CLR/RAMP1 are plated in complete growth medium at 85,000 cells/well in 96-well poly-D-lysine-coated plates and cultured for 19 h before assay. Cells are washed with PBS and then incubated with inhibitor in the presence or absence of 50% human serum for 30 min at 37°C and 95% humidity in Cellgro Complete Serum-Free/Low-Protein medium with L-glutamine and 1 g/L bovine serum albumin. Isobutylmethylxanthine is added to the cells at a concentration of 300 μM and incubated for 30 min at 37°C. Human α-CGRP is added to the cells at a concentration of 0.3 nM and allowed to incubate at 37°C for 5 min. After α-CGRP stimulation, the cells are washed with PBS and processed for cAMP determination using the two-stage assay procedure according to the manufacturer's recommended protocol. Dose-response curves are plotted, and IC50 values are determined. |
Animal experiment: | Monkeys: Rhesus monkeys (male and female) weighing between 4 and 10 kg are anesthetized initially with ketamine (0.1 mL/kg i.m.) and then placed in the supine position on a temperature-controlled water circulating blanket and intubated with a 3-mm tracheal tube connected to 1-liter oxygen/1 to 2% isoflurane gas anesthesia. The right saphenous vein is cannulated for intravenous drug delivery, and blood samples are obtained from the left saphenous artery. Four rubber O-rings (8 mm inner diameter) are placed on the ventral side of the forearm without directly being positioned over a visible vessel. |
References: [1]. Salvatore CA, et al. Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther. 2008 Feb;324(2):416-21. Epub 2007 Nov 26. | |
| Cas No. | 781649-09-0 | SDF | |
| 别名 | N-[(3R,6S)-6-(2,3-二氟苯基)六氢-2-氧代-1-(2,2,2-三氟乙基)-1H-氮杂卓-3-基]-4-(2,3-二氢-2-氧代-1H-咪唑并[4,5-B]吡啶-1-基)-1-哌啶甲酰胺,Telcagepant;MK0974;MK 0974 | ||
| 化学名 | N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide | ||
| Canonical SMILES | C1CC(C(=O)N(CC1C2=C(C(=CC=C2)F)F)CC(F)(F)F)NC(=O)N3CCC(CC3)N4C5=C(NC4=O)N=CC=C5 | ||
| 分子式 | C26H27F5N6O3 | 分子量 | 566.54 |
| 溶解度 | DMSO: 10 mM,Ethanol: 1 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.7651 mL | 8.8255 mL | 17.651 mL |
| 5 mM | 0.353 mL | 1.7651 mL | 3.5302 mL |
| 10 mM | 0.1765 mL | 0.8826 mL | 1.7651 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet