MK-3207 HCl 化学構造
分子量: 594.05

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製品説明

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製品の説明

生物活性

製品説明 MK-3207 HClは、0.12nMのIC50によるカルシトニン遺伝子関連ペプチド(CGRP)受容体拮抗剤です。
ターゲット CGRP
IC50 0.12 nM [1]
In vitro試験 MK 3207 exhibits significantly higher affinity for both native and recombinant human CGRP receptor, as well as rhesus monkey CGRP receptor with Ki of 24 pM, ~24 pM and 22 pM, respectively, as compared to CGRP receptors from other species, including canine and rodent (Ki values of ~10 nM). Although has affinity for AMY1 (CTR/RAMP1) receptor with a Ki value of 0.75 nM, MK 3207 displays marked selectivity for human CGRP receptor versus related human AM1 (CLR/RAMP2) receptor, AM2 (CLR/RAMP3) receptor, AMY3 (CTR/RAMP3) receptor, and CTR with Ki values of 16.5 μM, 0.156 μM, 0.128 μM and 1.9 μM, respectively. MK 3207 potently inhibits human α-CGRP-induced cAMP production in HEK293 cells stably expressing human CLR/RAMP1 with an IC50 of 0.12 nM, and maintains similar potency in the presence of 50% human serum with an IC50 of 0.17 nM, indicating that the activity of MK 3207 would not be dramatically affected by plasma protein binding in vivo. MK 3207 exhibits approximately 65-fold more potent in the human serum-shifted in vitro functional assay than telcagepant with an IC50 of 10.9 nM. [1]
In vivo試験 Administration of MK 3207 produces a concentration-dependent inhibition of capsaicin-induced dermal vasodilation in rhesus monkeys, blocking the blood flow increase with an EC50 of 0.8 nM and an EC90 of 7 nM, respectively. MK 3207 displays approximately 100-fold more potent in the rhesus monkey CIDV assay versus telcagepant with an EC90 of 994 nM. [1]
臨床試験 A Phase II study to demonstrate the effectiveness and appropriate dosage level of MK 3207 in the treatment of acute migraine has been completed.
特集 The most potent orally active CGRP receptor antagonist described to date.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

In Vitro Functional Study HEK293 cells stably expressing the human CGRP receptor are preincubated with various concentrations of MK 3207 in the presence or absence of 50% human serum for 30 minutes at 37 °C. Isobutyl-methylxanthine (300 μM) is added to the cells, and then they are incubated for 30 minutes at 37 °C followed by stimulation with 0.3 nM α-CGRP for 5 minutes at 37 °C. After agonist stimulation cells are washed with PBS and the intracellular cAMP concentration is measured using the cAMP SPA Biotrak direct screening assay. Dose-response curve is plotted, and IC50 value is determined.

動物実験: [1]

動物モデル Adult rhesus monkeys (either sex) with capsaicin-induced dermal vasodilation
製剤 Dissolved in DMSO
投薬量 ~123.1 μg/kg
投与方法 Intravenous bolus followed by 25 minutes continuous intravenous infusion

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download MK-3207 HCl SDF
分子量 594.05
化学式

C31H29F2N5O3.HCl

CAS No. 957116-20-0
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 119 mg/mL (200.31 mM)
エタノール 119 mg/mL (200.31 mM)
5 mg/mL (8.41 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 6,9-Diazaspiro[4.5]decane-9-acetamide, 8-(3,5-difluorophenyl)-10-oxo-N-[(2R)-1,1',2',3-tetrahydro-2'-oxospiro[2H-indene-2,3'-[3H]pyrrolo[2,3-b]pyridin]-5-yl]-, hydrochloride

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