MK-0974CGRP receptor antagonist CAS# 781649-09-0 |
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Quality Control & MSDS
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| Cas No. | 781649-09-0 | SDF | Download SDF |
| PubChem ID | 11319053 | Appearance | Powder |
| Formula | C26H27F5N6O3 | M.Wt | 566.54 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Telcagepant | ||
| Solubility | DMSO : ≥ 50 mg/mL (88.26 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 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 | ||
| 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 | ||
| Standard InChIKey | CGDZXLJGHVKVIE-DNVCBOLYSA-N | ||
| Standard InChI | InChI=1S/C26H27F5N6O3/c27-18-4-1-3-17(21(18)28)15-6-7-19(23(38)36(13-15)14-26(29,30)31)33-24(39)35-11-8-16(9-12-35)37-20-5-2-10-32-22(20)34-25(37)40/h1-5,10,15-16,19H,6-9,11-14H2,(H,33,39)(H,32,34,40)/t15-,19-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | MK-0974(Telcagepant) is a highly potent, selective, and orally bioavailable antagonist of CGRP receptor with Ki values of 0.77 nM and 1.2 nM for human and rhesus CGRP receptors respectively. | |||||
| Targets | CGRP receptor | |||||
| IC50 | 0.77 nM and 1.2 nM (Human and rhesus CGRP,Ki) | |||||
MK-0974 Dilution Calculator
MK-0974 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.7651 mL | 8.8255 mL | 17.651 mL | 35.302 mL | 44.1275 mL |
| 5 mM | 0.353 mL | 1.7651 mL | 3.5302 mL | 7.0604 mL | 8.8255 mL |
| 10 mM | 0.1765 mL | 0.8826 mL | 1.7651 mL | 3.5302 mL | 4.4128 mL |
| 50 mM | 0.0353 mL | 0.1765 mL | 0.353 mL | 0.706 mL | 0.8826 mL |
| 100 mM | 0.0177 mL | 0.0883 mL | 0.1765 mL | 0.353 mL | 0.4413 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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.
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Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries.[Pubmed:20164785]
J Cardiovasc Pharmacol. 2010 May;55(5):518-21.
Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.
ACS chemical neuroscience molecule spotlight on Telcagepant (MK-0974).[Pubmed:22816019]
ACS Chem Neurosci. 2011 Jul 20;2(7):334-5.
Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html). MK-0974 is currently being studied in phase III clinical trials.
Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries.[Pubmed:20573757]
J Pharmacol Exp Ther. 2010 Sep 1;334(3):746-52.
The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (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]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.
Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine.[Pubmed:23798725]
Cephalalgia. 2013 Dec;33(16):1292-301.
OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.
