The large number of recent animal and clinical studies outlined within this application raises the possibility that highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor (mAChR) may provide a novel approach in the treatment of cognitive disturbances and negative symptoms commonly associated with schizophrenia. The discovery of VU0467319 as a highly selective M1 PAM, which display properties indicative of a preclinical drug candidate, provides an opportunity to advance it to nonclinical safety testing for ultimate clinical assessment. Key requirements for the continued development of a successful clinical therapeutic includes a favorable safety and tolerability profile in nonclinical species and a predicted human pharmacokinetic profile amenable to oral dosing in healthy volunteers. In Project 3 we propose to synthesize VU0467319 with appropriate certificates-of-analysis and GMP standards in order to characterize the safety and pharmacodynamics of VU0467319 in preclinical and clinical studies, the approach of which satisfying the expectations and guidance of both US and nonUS regulatory agencies. Preclinical safety studies will be conducted in rats and dogs to assess the safety and tolerability of VU0467319, and its metabolites, in preparation for a Phase I clinical trial. The assessment of the mutagenicity and clastogenicity potential, the overt organ toxicity, and the safety pharmacological profile for VU0467319 represents the primary deliverables of our preclinical drug development program. A successful safety and toxicity assessment will result in the filing of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) in support of a Phase I clinical trial. Should a toxicity or adverse pharmacology risk be identified, an advantage of our approach is the real-time data availability to Project 2 and the influence of the finding on the design of a backup M1 PAM candidate.
Presently, no M1 activating drug is approved for the treatment of schizophrenia. We propose to conduct studies that will contribute to the progression of VU0467319 from preclinical candidate status to an experimental clinical therapeutic, suitable for an assessment of human safety and tolerability of our drug candidate, as well as an early read of the pharmacodynamics of M1 activation. These efforts are critical to advancing future proof- of-concept studies which will establish selective M1 activation as a viable therapeutic approach in the treatment of schizophrenia.
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