The Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) has a mission to promote the translation of advances in basic science towards novel therapeutics. They have recruited faculty and staff with experience at over 10 different pharmaceutical companies to ensure a diverse set of approaches, techniques and philosophies to advancing compounds. Together they aim to de-risk drug discovery programs.
About the Target
Metabotropic Glutamate Receptor 5 (mGlu5) has been linked to numerous different diseases in preclinical models. Some of these have been extensively studied, like Fragile X Syndrome, while others are developing as more promising targets. The two newer targets for their small molecule mGlu5 NAM therapeutics are:
- Depressive Disorders (Pharmacol. Biochem. Behav. 2005, 81, 901)
- Including Major Depressive Disorder and Treatment Resistant Depression
- Parkinson’s disease (Neuropharmacology 2010, 58, 981)
- More specifically attenuation of L-DOPA induced Dyskinesia (Movement Disorders 2011, 26, 1243)
Preclinical Candidate Status
- Molecular Pharmacology
- Excellent mGlu5 NAM functional potency
- Fully competitive at the MPEP binding site
- Excellent selectivity against other mGlu receptors
- Eurofins PanLabs LeadProfiling Screen®: No significant responses noted at 10micromolar
- Behavioral Pharmacology
- Efficacy in multiple rodent models using IP and/or PO dosing
- Clean profile in rotarod and Irwin screens
- Drug Metabolism and Pharmacokinetics
- Low clearance and good bio-availability in rodent and non-rodents
- Good permeability and no efflux
- Limited drug-drug interaction potential
- No evidence of time dependent inhibition of P450 enzymes
- Low predicted human clearance
- Negative Ames test (+/-S9)
- Clean profile in cell-based cytotoxicity assays
- No hERG or other ion channel inhibition liabilities
- Single dose MTD studies completed in rodent and non-rodents
- Seven day DRF study in rats completed with no adverse findings
For more specific details please contact.
The two compounds, which are competition and still in development, are based on the MPEP scaffold, which includes a potential liability of an alkyne group. Neither the lead nor backup series for the VCNDD’s program have this liability. They are derived from a different scaffold.
Basimglurant- Roche – Discontinued Fragile X Syndrome Trial and now have a Treatment Resistant Depression Phase II trial ongoing.
Mavoglurant – Novartis – Discontinued Fragile X Syndrome Trial and now have an OCD Phase II trial ongoing.