MK-3207 HCl 957116-20-0_CGRP Receptor_GPCR & G Protein_Signaling Pathways_Products

MK-3207 HCl (MK-3207; MK3207), the hydrochloride salt of MK3207, is a novel, potent and orally bioactive CGRP (Calcitonin gene related peptide) receptor antagonist with important biological activity. It exhibits CGRP at IC50 and Ki of 0.12 nM and 0.022 nM, respectively.

Physicochemical Properties

Molecular Formula

C31H29F2N5O3.HCL

Molecular Weight

594.05

Exact Mass

593.2

CAS #

957116-20-0

Related CAS #

MK-3207;957118-49-9

PubChem CID

49867927

Appearance

Off-white to pink solid powder

LogP

5.052

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

1040

Defined Atom Stereocenter Count

SMILES

C1CCC2(C1)C(=O)N([C@@H](CN2)C3=CC(=CC(=C3)F)F)CC(=O)NC4=CC5=C(C[C@@]6(C5)C7=C(NC6=O)N=CC=C7)C=C4.Cl

InChi Key

VWKNXYACOMQRBX-KZCKSIIFSA-N

InChi Code

InChI=1S/C31H29F2N5O3.ClH/c32-21-10-19(11-22(33)13-21)25-16-35-31(7-1-2-8-31)29(41)38(25)17-26(39)36-23-6-5-18-14-30(15-20(18)12-23)24-4-3-9-34-27(24)37-28(30)40;/h3-6,9-13,25,35H,1-2,7-8,14-17H2,(H,36,39)(H,34,37,40);1H/t25-,30+;/m0./s1

Chemical Name

2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide;hydrochloride

Synonyms

MK-3207 Hydrochloride; MK-3207; MK3207; MK 3207

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

CGRP receptor ( IC50 = 0.12 nM )

ln Vitro

In vitro activity: MK-3207 exhibits a rhesus monkey receptor affinity (Ki) of 0.024±0.001 nM; n=14) that is comparable to that of humans, but its affinity for the canine and rat receptors is >400-fold lower, at 10 nM and 10±1.2 nM, respectively. With Ki values of 16,500 nM and 156±17 nM, respectively, MK-3207 exhibits high selectivity against the human AM1 (CLR/RAMP2) and AM2 (CLR/RAMP3) receptors. At 1.9±0.58 μM, MK-3207 exhibits a high level of selectivity against human CTR. With a Ki value of 128±25 nM, MK-3207 demonstrates good selectivity against the AMY3 (CTR/RAMP3) receptor as well. However, its Ki value of 0.75±0.13 nM indicates less selectivity against the AMY1 (CTR/RAMP1) receptor. MK-3207 potently inhibits human α-CGRP-stimulated cAMP responses in human CGRP receptor-expressing HEK293 cells, with an IC50 value of 0.12±0.02 nM. MK-3207 exhibits a significantly lower potency for the rat CGRP receptor, with a pIC50=7.31±0.09.

ln Vivo

MK-3207 profoundly activates central receptors because it is a CNS-penetrant. Following a 10 mg/kg oral dose of MK-3207, the ratio of CSF to plasma is 2 to 3%[1].

Enzyme Assay

MK-3207 and 40 pM rat amylin are combined in amylin binding assays, and then 25 μg of CTR/RAMP1 or 25 μg of CTR/RAMP3 membranes are added. The mixture is then incubated for three hours at room temperature in binding buffer (10 mM HEPES, 5 mM MgCl₂, and 0.2% bovine serum albumin) in a volume of one milliliter. As the radioligand in calcitonin binding assays, 25 μg of CTR membranes are used with 30 pM ¹²⁵I-human calcitonin. Filtration through GF/B 96-well filter plates blocked with 0.5% polyethylenimine ends the incubation process. Prism is utilized for data analysis, and the equation Ki=IC50/1 + ([ligand]/K_D is used to calculate the Ki value. Saturation binding experiments are used to calculate the K_D value for each receptor.

Animal Protocol

A specially made flexible silicone catheter is fed into a surgically implanted port body in the midscapular region after being fully suspended in the cisterna magna and securely anchored on both sides of the atlanto-occipital membrane. The catheter is tunneled subcutaneously to this location. Via the skin and membrane covering the port, a needle is aseptically inserted to access the CSF; peripheral venipuncture is used to obtain blood samples. 0.5, 1, 2, 4, 8, and 24 hour CSF and plasma samples are taken and subjected to compound level analysis following oral administration of MK-3207 at 10 mg/kg (0.5% methylcellulose, with an adjusted pH of approximately 3) to rhesus monkeys with port-implanted cisterna magna catheters.

References

[1]. Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther. 2010 Apr;333(1):152-60.

Solubility Data

Solubility (In Vitro)

DMSO: ~119 mg/mL (~200.3 mM)

Water: ~5 mg/mL (~8.4 mM)

Ethanol: ~119 mg/mL (~200.3 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.5 mg/mL (4.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

Solubility in Formulation 3: ≥ 2.5 mg/mL (4.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.6834 mL	8.4168 mL	16.8336 mL
	5 mM	0.3367 mL	1.6834 mL	3.3667 mL
	10 mM	0.1683 mL	0.8417 mL	1.6834 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

MK-3207 HCl 957116-20-0

CAS No.: 957116-20-0

Physicochemical Properties

Biological Activity

Solubility Data