A large number of anatomical, molecular, genetic, preclinical behavioral and human clinical studies have provided strong evidence that agents able to enhance cholinergic transmission or activate muscarinic acetylcholine receptors (mAChRs, M1-M5), notably M1, have exciting therapeutic potential for the treatment of the positive, negative and cognitive symptoms of schizophrenia as well as cognitive dysfunction in other CNS disorders. However, previous compounds developed to selectively activate M1 receptors have failed in clinical development due to a lack of true specificity for M1 and adverse effects associated with activation of other mAChR subtypes (M2, M3). Furthermore, the lack of highly selective compounds has made it impossible to definitively determine whether the behavioral and clinical effects of these compounds are mediated by M1. During our initial NCDDG funding period, we developed multiple series of highly selective M1 positive allosteric modulators (PAMs) with unprecedented, clean ancillary pharmacology and DMPK profiles. To date, the majority of reported M1 PAMs are either weak PAMs or very potent PAMs with allosteric agonist activity (ago- PAMs), with limited solubility and poor CNS exposure (B:P ratios <0.3). With these issues in mind, we advanced multiple HTS leads into chemical optimization during the initial NCDDG funding period, resulting in nine composition of matter patent filings for novel M1 PAM chemotypes. Our M1 PAM series differentiate from the known art by displaying improved solubility, possessing both pure PAM and more modest ago-PAM pharmacological profiles, and importantly, excellent CNS exposure (B:P ratios 0.65 to 1.3) enabling both detailed in vivo evaluation in cognition models and a path towards a biomarker strategy. While we have a preclinical candidate in hand (VU0467319), a successful clinical program will require active chemistry to prepare large scale (single-batch) quantities of VU0467319 for non-GLP pharmacology, biomarker and DMPK studies to support the ongoing IND-enabling studies, as well as a backup program. Many drugs on the market today that are blockbusters were the second or third compound advanced into IND-enabling or clinical testing, brought forward to replace a ?first in class? prototype that failed at various stages in development. Backup programs can focus on either the same chemotype and improve perceived liabilities with the current candidate (or address known liabilities as data from either IND-enabling studies or clinical data become available), and/or a novel chemotype to prepare for non-mechanism-based, chemotype-specific liabilities that may arise in development. The absolute necessity of a backup effort is well appreciated in industry to enhance the chances that a program will result in robust target validation in man and the development of a marketed product. Thus, M1 PAMs, with the appropriate profile and drug-like properties, may represent a fundamentally new approach for the treatment of the negative symptoms and cognitive dysfunction in schizophrenic patients; therefore, we must position ourselves to be successful with a strong backup effort.
M1 PAMs, with the appropriate profile and drug-like properties, may represent a fundamentally new approach for the treatment of the negative symptoms and cognitive dysfunction in schizophrenic patients. A successful program for advancing M1 PAMs into clinical studies will require active chemistry to prepare large scale (single- batch) quantities of the clinical candidate, VU0467319, for non-GLP pharmacology, biomarker and DMPK studies to support the ongoing IND-enabling studies, as well as a strong backup program. Project 2 will focus on providing a high quality supply of VU0467319 and robust backup program to position this effort to be successful in fully evaluating M1 PAMs for treatment of schizophrenia.
