Available treatments for schizophrenia are not effective in treatment of all major symptoms associated with the disease and induce 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. During the initial funding period of the Vanderbilt NCDDG for discovery of novel treatments for schizophrenia, we made tremendous progress in discovery of drug candidates for novel targets and partnering with pharmaceutical companies to advance these agents to clinical development. In addition, we built on previous clinical studies suggesting that selective activators of the M1 muscarinic acetylcholine receptor have potential for treatment of cognitive disturbances and negative symptoms associated with schizophrenia. We optimized novel highly selective M1 positive allosteric modulators (PAMs) and have extensively evaluated these compounds in animal models of cognitive function and in pre-GLP safety studies. We have identified VU0467319 as a highly optimized M1 PAM that possesses an excellent balance of properties required for selection as a clinical development candidate. We now propose continued support of the Vanderbilt NCDDG to advance VU0467319 into first in human studies and to rigorously establish the doses required to achieve activation of M1 in healthy human volunteers. Project 1 will develop and validate a new translational biomarker for M1 PAM activity that can be used as a surrogate for target engagement and dose-finding studies in early clinical development. Project 2 will provide scale-up synthesis of VU0467319 and other compounds and provide backup clinical candidates to respond to findings with VU0467319 during GLP safety assessment. Project 3 will focus on IND-enabling studies to open an IND to allow clinical evaluation of VU0467319. In Project 4, we will perform safety assessments of VU0467319 in healthy human volunteers and employ the biomarker developed in project 1 to establish the doses required to achieve adequate CNS activity in humans. In addition, project 4 will provide a preliminary assessment of effects of VU0467319 on cognitive function in humans. These studies will provide a fully validated clinical research tool for future clinical studies to fully evaluate the efficacy of a highly optimized M1 PAM in schizophrenia patients.

Public Health Relevance

Successful completion of this program has the potential to have a transformative impact on the standard of care for schizophrenia patients. This highly interdisciplinary effort is directly focused on the overall goals and strategic plan of the NIMH. These studies will provide critical information in clinically validating a new drug target and will provide a highly optimized clinical research tool that can be used to advance M1 PAMs for treatment of schizophrenia and other brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19MH106839-01
Application #
8877102
Study Section
Special Emphasis Panel (ZMH1-ERB-C (01))
Program Officer
Brady, Linda S
Project Start
2015-09-10
Project End
2018-06-30
Budget Start
2015-09-10
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$2,072,400
Indirect Cost
$752,400
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Rook, Jerri M; Bertron, Jeanette L; Cho, Hyekyung P et al. (2018) A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity. ACS Chem Neurosci 9:2274-2285
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
Berizzi, Alice E; Bender, Aaron M; Lindsley, Craig W et al. (2018) Structure-Activity Relationships of Pan-G?q/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators. ACS Chem Neurosci 9:1818-1828
Bender, Aaron M; Cho, Hyekyung P; Nance, Kellie D et al. (2018) Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold. ACS Chem Neurosci 9:1572-1581
Rook, Jerri M; Abe, Masahito; Cho, Hyekyung P et al. (2017) Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs. ACS Chem Neurosci 8:866-883
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
Panarese, Joseph D; Cho, Hykeyung P; Adams, Jeffrey J et al. (2016) Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration. Bioorg Med Chem Lett 26:3822-5