VU 0357121

• CAT Number: I003545
• CAS Number: 433967-28-3
• Molecular Formula: C17H17F2NO2
• Molecular Weight: 305.325
• Purity: ≥95%
• Synonyms: 4-butoxy-N-(2,4-difluorophenyl)benzamide
• Target: mGluR
• Solubility: DMSO 60 mg/mL; Water <1 mg/mL
• Storage: 3 years -20C powder
• IC50: 33 nM(EC50)
• InChI: InChI=1S/C17H17F2NO2/c1-2-3-10-22-14-7-4-12(5-8-14)17(21)20-16-9-6-13(18)11-15(16)19/h4-9,11H,2-3,10H2,1H3,(H,20,21)
• InChIKey: AHCYOTLTLQTPSU-UHFFFAOYSA-N
• SMILES: CCCCOC1=CC=C(C=C1)C(=O)NC2=C(C=C(C=C2)F)F

VU0357121 is a novel positive and highly selective allosteric modulator (PAM) of mGlu5R with EC50 of 33 nM.IC50 Value: 33 nM(EC50)Target: mGluR5in vitro: VU0357121 do not bind at the MPEP allosteric site of mGlu5, thus do not possess mGlu5 NAM activity. The A809V/rmGlu5 mutation inhibited the ability of VU0357121 to shift the glutamate concentrationresponse curve, whereas the response to VU0357121 is not altered by the F585I/rmGlu5 mutation. VU0357121 show weaker cooperativity in the Ca2+ mobilization assay in the low-expressing HEK293A-mGlu5 cell line.in vivo:

Reference

[1]. Hammond, Alexis S.; Rodriguez, Alice L.; Townsend, Steven D. et al. Discovery of a Novel Chemical Class of mGlu5 Allosteric Ligands with Distinct Modes of Pharmacology. ACS Chemical Neuroscience (2010), 1(10), 702-716.
Abstract
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC(50) = 1.3 μM, 106% Glu(max)) and VU0040237 (EC(50) = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.