Synonym
VU0430644; VU-0430644; VU 0430644; VU0430644-2; ML254; ML 254; ML-254;
IUPAC/Chemical Name
5-[2-(3-fluorophenyl)ethynyl]-N-(3-methyloxetan-3-yl)pyridine-2-carboxamide
InChi Key
YMYCVXPMSMNWEP-UHFFFAOYSA-N
InChi Code
InChI=1S/C18H15FN2O2/c1-18(11-23-12-18)21-17(22)16-8-7-14(10-20-16)6-5-13-3-2-4-15(19)9-13/h2-4,7-10H,11-12H2,1H3,(H,21,22)
SMILES Code
O=C(C1=NC=C(C#CC2=CC=CC(F)=C2)C=C1)NC3(C)COC3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
ML-254, also known as VU0430644; is Positive Allosteric Modulators (PAMs) of mGlu5 with Competitive MPEP-Site Interaction.
In vitro activity:
ML-254, also known as VU0430644; is Positive Allosteric Modulators (PAMs) of mGlu5 with Competitive MPEP-Site Interaction.To validate that 38t (ML-254) interacts with mGlu5 at the MPEP binding site radioligand binding studies were performed with [3H]methoxyPEPy. Increasing concentrations of 38t resulted in complete inhibition of [3H]methoxyPEPy binding supporting a competitive interaction between the two ligands (Figure 9). 38t (ML-254) exhibited a Ki of 90 nM, representing a ~10-fold higher functional activity (EC50 = 9.3 nM) compared to binding. In addition, screening of 10 µM 38t against a panel of 68 GPCRs, ion channels and transporters revealed no significant off target activity (Eurofins Inc.).
Reference: J Med Chem. 2013 Oct 24;56(20):7976-96. https://pubmed.ncbi.nlm.nih.gov/24050755/
In vivo activity:
Rat brain homogenate binding was used to determine fraction unbound in brain for 38t (ML-254); these studies revealed fu brain values of 1.6%. To assess drug-drug interactions, inhibition of the major human cytochrome P450 (CYP) enzymes (2C9, 2D6, 3A4, 1A2) was measured in human liver microsomes and 38t was found to display inhibitory activity at 1A2 (IC50 = 5.30 µM) while no activity was observed against the other CYPs tested (IC50 >30 µM). Solubility of 38t was found to be modest with a Fassif (fasted simulated intestinal fluid) solubility of 10–23 µg/mL.
Reference: J Med Chem. 2013 Oct 24;56(20):7976-96. https://pubmed.ncbi.nlm.nih.gov/24050755/
Preparing Stock Solutions
The following data is based on the
product
molecular weight
310.33
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, Gregory KJ, Vinson PN, Rook JM, Gogi KK, Xiang Z, Bridges TM, Daniels JS, Jones C, Niswender CM, Meiler J, Conn PJ, Lindsley CW, Stauffer SR. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254). J Med Chem. 2013 Oct 24;56(20):7976-96. doi: 10.1021/jm401028t. Epub 2013 Oct 9. PMID: 24050755; PMCID: PMC3908770.
In vitro protocol:
Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, Gregory KJ, Vinson PN, Rook JM, Gogi KK, Xiang Z, Bridges TM, Daniels JS, Jones C, Niswender CM, Meiler J, Conn PJ, Lindsley CW, Stauffer SR. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254). J Med Chem. 2013 Oct 24;56(20):7976-96. doi: 10.1021/jm401028t. Epub 2013 Oct 9. PMID: 24050755; PMCID: PMC3908770.
In vivo protocol:
Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, Gregory KJ, Vinson PN, Rook JM, Gogi KK, Xiang Z, Bridges TM, Daniels JS, Jones C, Niswender CM, Meiler J, Conn PJ, Lindsley CW, Stauffer SR. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254). J Med Chem. 2013 Oct 24;56(20):7976-96. doi: 10.1021/jm401028t. Epub 2013 Oct 9. PMID: 24050755; PMCID: PMC3908770.
Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, Gregory KJ, Vinson PN, Rook JM, Gogi KK, Xiang Z, Bridges TM, Daniels JS, Jones C, Niswender CM, Meiler J, Conn PJ, Lindsley CW, Stauffer SR. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254). J Med Chem. 2013 Oct 24;56(20):7976-96. doi: 10.1021/jm401028t. Epub 2013 Oct 9. PMID: 24050755; PMCID: PMC3908770.
