Major Depressive Disorder (MDD) affects approximately 16% of Americans and represents one of the most common causes of disability worldwide. Unfortunately, less than one third of patients experience sustained remission of MDD symptoms with currently available medications. Recent studies have raised the exciting possibility that highly selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate receptor mGlus subtype may provide a novel approach to the treatment of MDD. This mechanism represents a fundamental departure from existing therapies and has the potential to provide more rapid onset than existing therapies and may provide sustained relief for refractory patients. In this revised NCDDG application, we propose studies aimed at using our novel mGlus NAMs discovered at the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) to further validate this mechanism in animal models and perform translational studies that can support a future clinical development effort. In addition, we will optimize novel mGlus NAMs to achieve properties required to select a lead clinical development candidate and backup compounds. This will require coordinated efforts of two major projects and support of 2 cores. Project 1 will focus on animal studies aimed at further characterizing the behavioral effects and CNS occupancy of novel mGlus NAMs. In Project 2, we will chemically optimize novel mGlus NAMs based on this scaffold to achieve a balance of properties required to select a clinical development candidate that can advance to IND-enabling studies and clinical development. These projects will be supported by two cores, including a Bioanalytical and DMPK Core (Core A) and Administrative Core (Core B).
Successful completion of this highly interdisciplinary effort will provide critical preclinical information for the validation of a novel therapeutic strategy through antagonism of mGluR5 for the potential treatment of symptoms associated with MDD and a highly optimization of mGlus NAM preclinical candidate and backups for future clinical studies in MDD patients.
|Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2017) Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett 27:4858-4866|
|Felts, Andrew S; Rodriguez, Alice L; Blobaum, Anna L et al. (2017) Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation. J Med Chem 60:5072-5085|
|Nickols, Hilary Highfield; Yuh, Joannes P; Gregory, Karen J et al. (2016) VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy. J Pharmacol Exp Ther 356:123-36|
|Lindsley, Craig W; Emmitte, Kyle A; Hopkins, Corey R et al. (2016) Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors. Chem Rev 116:6707-41|
|Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2016) N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents. Bioorg Med Chem Lett 26:1894-900|
|Gould, Robert W; Amato, Russell J; Bubser, Michael et al. (2016) Partial mGlu? Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects. Neuropsychopharmacology 41:1166-78|
|Nedelcovych, Michael T; Gould, Robert W; Zhan, Xiaoyan et al. (2015) A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances. ACS Chem Neurosci 6:485-93|
|Gregory, Karen J; Nguyen, Elizabeth D; Malosh, Chrysa et al. (2014) Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem Neurosci 5:282-95|
|Nickols, Hilary Highfield; Conn, P Jeffrey (2014) Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis 61:55-71|
|Cho, Hyekyung P; Engers, Darren W; Venable, Daryl F et al. (2014) A novel class of succinimide-derived negative allosteric modulators of metabotropic glutamate receptor subtype 1 provides insight into a disconnect in activity between the rat and human receptors. ACS Chem Neurosci 5:597-610|
Showing the most recent 10 out of 22 publications