The incidence and significance of central nervous system diseases are increasing at an alarming rate all over the world. Although substantial research efforts have been applied to develop new drugs, only a few CNS disorders are more or less satisfactorily addressed, while remaining pose significant clinical challenges. The most important factor limiting the development of new drugs for the central nervous system (CNS) is the blood–brain barrier (BBB). Optimizing the distribution of therapeutic compounds between brain and blood is one of the key issues in the design of novel CNS-active drugs. Recently, it has been estimated that BBB permeability depends on the MW of a drug, its charge, and lipophilicity. The latter is reflected by the ability of a compound to form hydrogen bonds that limit its diffusion through the BBB. CNS drugs tend to be more lipophilic and less flexible (number of rotatable bonds < 8), to have fewer hydrogen-bond donors (< 3) and acceptors (< 7), reduced MW, fewer formal charges (particularly, negative charges) and lower polar surface area.
The Life Chemicals CNS Library comprises over 7,000 carefully selected small organic molecules that meet parameters listed in the table below. PAINS and toxicophore filters were also applied to the Library. Calculations were done using the SYBYL-X software:
|MW||150 – 400|
|ClogP||1.3 – 3.0|
|PSA||≤ 65 Å2|
|Rings||1 – 5|
|Total H-bonding||< 8|
|Carboxylic acid group||≤ 1|
|S atoms||≤ 2|
|Cl atoms||≤ 2|
|Basic Nitrogen||≤ 2|
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