Abstract

The Bioanalytical and DMPK Core will provide high throughput in vitro screening and LC/MS/MS bioanalytical support in the following discovery and preclinical development Projects (1, 2) identified within this application: 1) perform the Tier 1 DMPK screening of; 2) perform the rodent PK assessment and subsequent bioanalysis of mGlu5 NAM discovery compounds as well as assess the PK properties of compounds testing externally in dogs and nonhuman primates; and 3) perform the bioanalysis of biological media originating from the behavioral pharmacology assessment of mGIU5 discovery candidates in rodent models of depression, as well as establish PK/PD relationships of said studies. Built with key personnel possessing experience from the pharmaceutical industry, specifically from drug metabolism and pharmacokinetic (PK) research and development experience, the Core will aid in PK study design, coordinate the receipt and storage of biological media samples originating from preclinical pharmacology, definitive PK studies and nonpivotal toxicity studies, as well as plasma and urine samples originating from Phase 1 clinical studies. The Core will also implement the Tier 1 DMPK screen, including subsequent in vitro bioanalysis. The DMPK scientist will adopt a contemporary approach to LC/MS/MS based bioanalysis employing state-of-the-art mass spectrometry and liquid chromatography equipment and an adherence to regulatory guidances appropriate for the nonGLP PK studies. Finally, Dr. Daniels and his DMPK team will perform PK analysis of the data employing industry-standard software capable of modeling time concentration profiles generated from nonclinical studies.

Public Health Relevance

The Bioanalytical and DMPK Core will provide assistance to the principal investigators (Pis) linked to the respective Projects within the application, specifically through the screening of mGIUs discovery NAMs for DMPK attributes and exposure determination from investigations in rat models of depression. By providing PK expertise across this interdisciplinary set of Projects, the DMPK Core will be able to influence the successful transition of lead mGIUs NAM compounds from a discovery stage to the preclinical development setting, an experience certain to facilitate similar transitions of neuropharmacology programs within the VCNDD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH097056-03
Application #
8788724
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240

  Publications

Doria, Juliana G; de Souza, Jessica M; Silva, Flavia R et al. (2018) The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. J Neurochem 147:222-239
Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2018) Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett 28:1679-1685
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

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