MK-3207 HCl

Catalog No.S1542

MK-3207 is a potent CGRP receptor antagonist with IC50 and Kiof 0.12 nM and 0.022 nM, highly selective versus human AM1, AM2, CTR, and AMY3. Phase 2.

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MK-3207 HCl Chemical Structure

MK-3207 HCl Chemical Structure
Molecular Weight: 594.05

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MK-3207 HCl is available in the following compound libraries:

Product Information

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Product Description

Biological Activity

Description MK-3207 is a potent CGRP receptor antagonist with IC50 and Kiof 0.12 nM and 0.022 nM, highly selective versus human AM1, AM2, CTR, and AMY3. Phase 2.
Targets CGRP [1]
IC50 0.12 nM
In vitro 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 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]
Features The most potent orally active CGRP receptor antagonist described to date.

Protocol(Only for Reference)

Kinase Assay: [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.

Animal Study: [1]

Animal Models Adult rhesus monkeys (either sex) with capsaicin-induced dermal vasodilation
Formulation Dissolved in DMSO
Dosages ~123.1 μg/kg
Administration 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 pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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

References

[1] Salvatore CA, et al. J Pharmacol Exp Ther, 2010, 333(1), 152-160.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00712725 Completed Migraine Merck Sharp & Dohme Corp. July 2008 Phase 2
NCT00548353 Completed Migraine Disorders Merck Sharp & Dohme Corp. August 2007 Phase 1

Chemical Information

Download MK-3207 HCl SDF
Molecular Weight (MW) 594.05
Formula

C31H29F2N5O3.HCl

CAS No. 957116-20-0
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 119 mg/mL (200.31 mM)
Ethanol 119 mg/mL (200.31 mM)
Water 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.
Chemical Name 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

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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