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.
A major research center like the Superfund Research Program requires strong leadership, management, organizational skills and fiscal management to achieve its scientific and community related goals. The experienced leadership in this Administrative Core has experience in leading a complex yet highly productive program that has garnered extraordinary support from its government and community partners. The Core is poised to continue this leadership in the next grant cycle. RELEVANCE (See instructions): A major research center like the Superfund Research Program requires strong leadership, management, organizational skills and fiscal management to achieve its scientific and community related goals. The experienced leadership in this Administrative Core has experience in leading a complex yet highly productive program that has garnered extraordinary support from its government and community partners. The Core is poised to continue this leadership in the next grant cycle.
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|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|
|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|
|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|
|Wood, Michael R; Noetzel, Meredith J; Melancon, Bruce J et al. (2017) Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia. ACS Med Chem Lett 8:233-238|
|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|
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