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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH097056-02
Application #
8603877
Study Section
Special Emphasis Panel (ZMH1-ERB-C)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$302,072
Indirect Cost
$108,436
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Cho, Hyekyung P; Garcia-Barrantes, Pedro M; Brogan, John T et al. (2014) Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. ACS Chem Biol 9:2334-46
Conn, P Jeffrey; Lindsley, Craig W; Meiler, Jens et al. (2014) Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13:692-708
Bates, Brittney S; Rodriguez, Alice L; Felts, Andrew S et al. (2014) Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorg Med Chem Lett 24:3307-14
Nickols, Hilary Highfield; Conn, P Jeffrey (2014) Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis 61:55-71
Amato, Russell J; Felts, Andrew S; Rodriguez, Alice L et al. (2013) Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction. ACS Chem Neurosci 4:1217-28
Lovell, Kimberly M; Felts, Andrew S; Rodriguez, Alice L et al. (2013) N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: identification of VU0469650, a potent and selective tool compound with CNS exposure in rats. Bioorg Med Chem Lett 23:3713-8