ML-254
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MedKoo CAT#: 555938

CAS#: 1428630-86-7

Description: ML-254, also known as VU0430644; is Positive Allosteric Modulators (PAMs) of mGlu5 with Competitive MPEP-Site Interaction. ML254 is highly selective for mGlu5 versus other mGlu receptors, has a clean ancillary Ricerca profile, and suitable dystrophia myotonica protein kinase (DMPK) properties for systemic dosing in rodents. Preliminary experiments at a single dose in an in vivo model of psychosis using ML254 demonstrates a robust reversal of amphetamine induced hyperlocomotion. ML254 will serve as a significant pure-PAM tool compound for the field with potential for studies within in vivo paradigms. Structure activity relationship (SAR) and characterization of ML254 are described.

Chemical Structure

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ML-254
CAS# 1428630-86-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 555938
Name: ML-254
CAS#: 1428630-86-7
Chemical Formula: C18H15FN2O2
Exact Mass: 310.11
Molecular Weight: 310.328
Elemental Analysis: C, 69.67; H, 4.87; F, 6.12; N, 9.03; O, 10.31

Price and Availability

Size Price Availability Quantity
25mg USD 250 2 Weeks
50mg USD 450 2 Weeks
100mg USD 750 2 Weeks
200mg USD 1250 2 Weeks
500mg USD 2250 2 Weeks
1g USD 3250 2 Weeks
2g USD 5450 2 Weeks
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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

Appearance: Solid powder

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

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Product Data:
Product Data
Instruction:
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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.

Recalculate based on batch purity %
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.

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