BMS-927711 (Synonyms: BMS-927711) |
| رقم الكتالوجGC13705 |
A CGRP receptor antagonist
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1289023-67-1
Sample solution is provided at 25 µL, 10mM.
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BMS-927711 is an orally potent CGRP receptor antagonist with IC50 of 0.14 nM. [1]
Calcitonin gene-related peptide CGRP is a 37 amino acid peptide widely distributed in the nervous system, which is a highly potent vasodilator that has been directly implicated in the pathology of migraine. Studies have revealed that plasma concentrations of CGRP are elevated during migraine attacks, and these levels could be normalized by sumatriptan in connection with the relief of headache. CGRP receptors are G-coupled cell surface receptors composed of the calcitonin receptor-like receptor (CLR), receptor activity modifying protein 1 (RAMP1), and the receptor component protein (RCP). BMS-927711 is an antagonist of CGRP receptor and could alleviate migraine. [1, 2]
Binding affinities for the human CGRP receptor were determined by inhibition of 125I-CGRP binding to SK-N-MC cell membranes, which endogenously express receptor. BMS-927711 was shown to be a full, competitive antagonist with IC 50 = 0.14±0.01 nM. Moreover, it showed excellent permeability in tests of PAMPA. Functional receptor antagonism for BMS-927711 was determined by measuring inhibition of CGRP-stimulated cAMP production in SK-N-MC cells. [1]
In a large Phase 2b study testing BMS-927711 for the acute treatment of migraine, an adaptive design to test six doses of BMS-927711 (10, 25, 75, 150, 300 and 600 mg) against placebo was adopted while Sumatriptan 100 mg was used as an active comparator. BMS-927711 was proved to be effective at multiple doses. For the primary endpoint, namely the proportion pain-free at 2 hours post dose, doses of 75 mg, 150 mg and 300 mg (as well as sumatriptan) were superior to placebo. However, 600mg showed no additional benefits over lower doses. Besides, efficacy was numerically inferior to sumatriptan for this endpoint for all doses. [2]
References:
[1]. Luo G, Chen L, Conway C M, et al. Discovery of (5 S, 6 S, 9 R)-5-Amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5 H-cyclohepta [b] pyridin-9-yl 4-(2-oxo-2, 3-dihydro-1 H-imidazo [4, 5-b] pyridin-1-yl) piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine[J]. Journal of medicinal chemistry, 2012, 55(23): 10644-10651.
[2]. Bigal M E. BMS-927711 for the acute treatment of migraine[J]. Cephalalgia, 2013: 0333102413500728.
Animal experiment: | Rats[2] Rats are treated with drug-free vehicle (control) or Rimegepant (BMS-927711) in vehicle at 60, 100, and 300 mg/kg once daily via oral gavage. There are 6 rats in each treatment group. For each treatment group, blood is collected at 1, 6, and 24 h from first three rats, and at 3 and 8 h from the second three rats on Day 1 and Day 14 from the tail vein following daily oral dosing of Rimegepant (BMS-927711) for two weeks. The mean hematocrits in the blood are 50.2±1.8%, 49.8±2.2%, 46.4±5.2% corresponding to the animal groups of 60, 100, and 300 mg/kg doses, respectively. For DBS evaluation, four 15 μL blood samples are spotted onto DBS cards (4 spots per card), dried at room temperature for at least 2 h, and each card is packaged separately in a ziplock bag with desiccant prior to shipment. The remaining blood in each sample tube is processed to plasma within 1 h of collection and stored at -70°C until analysis. Plasma samples are shipped on dry ice, and DBS cards are shipped at ambient temperature. Rimegepant (BMS-927711) concentrations in rat plasma are analyzed. Rimegepant in rat DBS is analyzed using the DBS method. The toxicokinetic (TK) parameters are calculated from blood concentration and time data using non-compartmental methods using Kinetica. |
References: [1]. Luo G, et al. Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. J Med Chem. 2012 Dec 13;55(23):10644-51. | |
| Cas No. | 1289023-67-1 | SDF | |
| المرادفات | BMS-927711 | ||
| Chemical Name | 5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate | ||
| Canonical SMILES | FC1=CC=CC(C2C(N)C(C=CC=N3)=C3C(OC(N4CCC(N5C6=C(N=CC=C6)NC5=O)CC4)=O)CC2)=C1F | ||
| Formula | C28H28F2N6O3 | M.Wt | 534.56 |
| الذوبان | DMF: 5 mg/ml,DMSO: 20 mg/ml,DMSO:PBS (pH 7.2) (1:4): 0.20 mg/ml | 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. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8707 mL | 9.3535 mL | 18.707 mL |
| 5 mM | 0.3741 mL | 1.8707 mL | 3.7414 mL |
| 10 mM | 0.1871 mL | 0.9353 mL | 1.8707 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Quality Control & SDS
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- Purity: >99.00%
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Average Rating: 5 (Based on Reviews and 30 reference(s) in Google Scholar.)
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