The Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) has a mission to promote the translation of advances in basic science towards novel therapeutics. They have recruited faculty and staff with experience at over 10 different pharmaceutical companies to ensure a diverse set of approaches, techniques and philosophies to advancing compounds. Together they aim to de-risk drug discovery programs.
Muscarinic Acetylcholine Receptor 1 (M1) has long been a target for the treatment of CNS diseases, specifically related to Alzheimer’s. Pathological changes and death of cholinergic neurons are amongst the earliest changes in Alzheimer’s disease patients, and AChE inhibitors are approved for the treatment of cognitive impairment in Alzheimer’s disease patients. M1 is highly expressed in the hippocampus and cortex, which are regions critical to cognitive function therefore, M1 has the potential to be a more specific therapeutic.
However, multiple efforts, from numerous companies have failed due to adverse effects mediated through the M2 and M3 receptors (bradycardia, GI distress, and excessive salivation and sweating). Muscarinic receptors have complex pharmacology, both in vivo and in vitro, which make identifying selective agents difficult. This has caused many programs to fail because they were believed to have selective agents, but in fact they were not. In addition, many agents reported to be allosteric, were bitopic and could engage the orthosteric binding pocket at higher doses, and thus also the M2 and M3 receptors, garnering the same side effects.
Summary of Advanced Lead Compounds
An Irwin battery test in rodents has demonstrated that none of the M2/3 mediated side effects are present. Additionally no observable SLUD effects were observed in non-human primates. The lead is currently undergoing IND-enabling studies and we anticipate an open IND in 2016.
Target Profile (table 1)
Additional details available upon request.
The only currently known competition is Merck’s compound MK-7622 is in Phase 2 trials. The selectivity of which is not predicted to be as good as the VCNDD advanced leads, or without SLUD effects.