781649-09-0
781649-09-0 structure
- Name: MK-0974
- 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
- CAS Number: 781649-09-0
- Molecular Formula: C26H27F5N6O3
- Molecular Weight: 566.523
- Catalog: Pharmaceutical intermediate Heterocyclic compound Pyridine compound Ethylpyridine
- Create Date: 2018-10-09 11:29:34
- Modify Date: 2024-01-02 12:28:15
-
MK-0974 is a calcitonin gene-related peptide (CGRP) receptor antagonist with Kis of 0.77 nM and 1.2 nM for human and rhesus CGRP receptors, respectively.
| 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 |
|---|---|
| Synonyms |
Telcagepant
1-piperidinecarboxamide, N-[(3R,6S)-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)- N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-3-azepanyl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxamide MK 0974 MK-0974 |
| Description | MK-0974 is a calcitonin gene-related peptide (CGRP) receptor antagonist with Kis of 0.77 nM and 1.2 nM for human and rhesus CGRP receptors, respectively. |
|---|---|
| Related Catalog | |
| Target |
Ki: 0.77 nM (human CGRP), 1.2 nM (rhesus CGRP) |
| In Vitro | MK-0974 displays affinity (Ki) for the canine and rat receptors, with values of 1204 nM and 1192 nM (n=10), respectively. MK-0974 potently blocks human α-CGRP-stimulated cAMP responses in human CGRP receptor expressing HEK293 cells with an IC50 of 2.2 nM[1]. MK-0974 displays saturable binding to SK-N-MC membranes with a KD of 1.9 nM and Bmax of 479 fmol/mg protein. MK-0974 also displays saturable binding to rhesus cerebellum homogenate with a KD of 1.3 nM and Bmax of 20 fmol/mg[2]. |
| In Vivo | MK-0974 (i.v. bolus, 1 mg/kg) demonstrates that the efficacy of this antagonist is time-dependent and correlated with plasma levels[1]. The pharmacokinetics of MK-0974 remains linear across 0.5-10 mg/kg intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) increase (5-30 mg/kg) is 15-fold over dose-proportional[3]. |
| Cell Assay | 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 Admin | 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 |
| Density | 1.5±0.1 g/cm3 |
|---|---|
| Molecular Formula | C26H27F5N6O3 |
| Molecular Weight | 566.523 |
| Exact Mass | 566.206482 |
| PSA | 103.33000 |
| LogP | 2.59 |
| Index of Refraction | 1.613 |
| Storage condition | 2-8℃ |