BMS-927711
(Synonyms: 瑞美吉泮,BMS 927711;BMS927711) 目录号 : GC13705
A CGRP receptor antagonist
Cas No.:1289023-67-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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. | |
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.
| Cas No. | 1289023-67-1 | SDF | |
| 别名 | 瑞美吉泮,BMS 927711;BMS927711 | ||
| 化学名 | 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 | ||
| 分子式 | C28H28F2N6O3 | 分子量 | 534.56 |
| 溶解度 | DMF: 5 mg/ml,DMSO: 20 mg/ml,DMSO:PBS (pH 7.2) (1:4): 0.20 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。 |
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| 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 | |||
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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 |
| 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。
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