Currently available antipsychotics for schizophrenia are not effective for the treatment of all major symptoms associated with the disease and are associated with a number of dose-limiting adverse effects. Thus, there is a critical need to develop novel therapeutic agents for treatment of schizophrenia that have broader efficacy and fewer adverse effects than currently available medications. We propose studies aimed at discovery and optimization of novel drug candidates for treatment of schizophrenia that are mechanistically unrelated to currently available antipsychotic agents and have the potential to provide efficacy in treatment of all major symptom clusters of this disease. The most advanced of these programs is focused on discovery of novel compounds that inhibit the glycine transporter 1, GlyT1. Glycine is a co-agonist with glutamate at the A/-methyl-D-aspartate (NMDA) subtype of glutamate receptors and provides an excellent approach to increasing NMDA receptor function while maintaining activity dependence of NMDA receptor activation. A number of clinical and animals studies suggest that GlyTI inhibitors have exciting potential for treatment of schizophrenia. To date, we have optimized novel scaffolds of GlyTI inhibitors with excellent pharmacokinetic and brain penetration profiles, robust efficacy in animal models, and lack significant toxicity. A second program is focused on discovery and optimization of highly selective allosteric agonists of the M1 muscarinic acetylcholine receptor. We have established a novel approach to development of highly selective agonists of the M1 muscarinic acetylcholine receptor by targeting allosteric sites and have shown that these compounds have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Both the Ml and GlyTI programs are based on strong validation from animal models and exciting clinical data that provide support for pursuing these novel targets. Our overall objective is to optimize drug candidates that interact with each of these targets. Ultimately, we will work with industry partners to develop these drug candidates in clinical studies. We will begin with lead optimization of GlyTI inhibitors, followed by hit-tc-lead and lead optimization of Ml allosteric agonists with a goal of advancing molecules that interact with each of these to a stage where they are ready for preclinical and clinical development. Finally, we have a pipeline of additional targets for which we have chemically diverse verified hits and early drug leads that are poised for full lead optimization efforts. While not specifically included in this application, this provides a robust discovery pipeline that will be important for the future directions of this program.

Public Health Relevance

The overarching goal of this proposal is to understand the cellular and molecular features of TLR2/NLR mediated responses, how these signaling events contribute to the host's ability to restrain bacterial growth, protective immunity, and how mAb bound to Ft and AAO Ft influences these immunological processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH087965-02
Application #
8230843
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$461,149
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Moran, Sean P; Cho, Hyekyung P; Maksymetz, James et al. (2018) PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems. ACS Chem Neurosci 9:2218-2224
Moran, Sean P; Dickerson, Jonathan W; Cho, Hyekyung P et al. (2018) M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition. Neuropsychopharmacology 43:1763-1771
Tarr, James C; Wood, Michael R; Noetzel, Meredith J et al. (2017) Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides. Bioorg Med Chem Lett 27:2990-2995
Bewley, Blake R; Spearing, Paul K; Weiner, Rebecca L et al. (2017) Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core. Bioorg Med Chem Lett 27:4274-4279
Lebois, Evan P; Schroeder, Jason P; Esparza, Thomas J et al. (2017) Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. ACS Chem Neurosci 8:1177-1187
Long, Madeline F; Engers, Julie L; Chang, Sichen et al. (2017) Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping. Bioorg Med Chem Lett 27:4999-5001
Bender, Aaron M; Weiner, Rebecca L; Luscombe, Vincent B et al. (2017) Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists. Bioorg Med Chem Lett 27:3576-3581
Wood, Michael R; Noetzel, Meredith J; Poslusney, Michael S et al. (2017) Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs. Bioorg Med Chem Lett 27:171-175
Bender, Aaron M; Weiner, Rebecca L; Luscombe, Vincent B et al. (2017) Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype. Bioorg Med Chem Lett 27:2479-2483
Melancon, Bruce J; Wood, Michael R; Noetzel, Meredith J et al. (2017) Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology. Bioorg Med Chem Lett 27:2296-2301

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