Over the last few years, the Central Nervous System Multi-Parameter Optimization (CNS MPO) algorithm has been applied prospectively to the design of novel brain-penetrant drug candidates. This design tool, which is based on six fundamental physicochemical properties commonly used by medicinal chemists, provides a flexible, multi-parameter approach rather than focusing on individual properties and hard cut-offs. The use of the CNS MPO has challenged design practices and has resulted in an expansion of the traditional CNS chemical space. It has been demonstrated that CNS candidates which show good brain penetration, ADME properties, and safety profiles can reside in a more polar, less lipophilic, less basic, and larger molecular weight space in comparison to marketed CNS drugs. This new desirability tool has thus challenged the dogma that CNS drugs need to be lipophilic with low polarity and has opened new space for different neuroscience target classes such as kinases and proteases.<br/><br/>Positron Emission Tomography (PET) ligands play a significant role in the CNS drug discovery process. PET ligands are important tools in measuring target occupancy and confirming access to the appropriate tissue in brain. In addition, these ligands have also been used in imaging disease stage and progression. With a goal of bringing a more rational approach to PET ligand development, application of the CNS MPO desirability tool has been extended to the design of novel PET ligands. A modified multi parameter optimization tool, CNS PET MPO, has been put in place together with other property criteria to allow rapid identification of quality PET ligand leads from hundreds of compounds and/or via highly focused structure-activity relationship (SAR) efforts. For each project, only 1-2 leads have been advanced to PET imaging studies to yield a successful PET ligand that performed well in the clinic.

Novel approaches in the design of CNS drug candidates and PET ligands

2019 Spring National Meeting

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