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CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure

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Eli Lilly and Company, 893 South Delaware Street, Indianapolis, Indiana 46285, United States
*Phone: +1 (317) 277-3179; E-mail: [email protected], [email protected]
Cite this: J. Med. Chem. 2015, 58, 6, 2584–2608
Publication Date (Web):December 11, 2014
https://doi.org/10.1021/jm501535r
Copyright © 2014 American Chemical Society

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    Abstract

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    The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.

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    Calculated physicochemical properties and CNS MPO scores for a diverse set of compounds with experimentally obtained Cu,b values (Figure 4). This material is available free of charge via the Internet at http://pubs.acs.org.

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