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CNS drug design: balancing physicochemical properties for optimal brain exposure.

Journal of medicinal chemistry (2014-12-17)
Zoran Rankovic
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Quinuclidine, 97%
Sigma-Aldrich
Ethanolamine, ACS reagent, ≥99.0%
Supelco
Ethanolamine, analytical standard
Supelco
Aucubin, analytical standard
Sigma-Aldrich
Ethanolamine, puriss. p.a., ACS reagent, ≥99.0% (GC/NT)
Sigma-Aldrich
Ethanolamine, ≥99%
Sigma-Aldrich
Ethanolamine, liquid, BioReagent, suitable for cell culture, ≥98%
Sigma-Aldrich
Ethanolamine, ≥98%
Sigma-Aldrich
Ethanolamine, purified by redistillation, ≥99.5%
SAFC
Ethanolamine
Aucubin, primary reference standard
Sigma-Aldrich
Quinidine, anhydrous
Supelco
Pyridine, analytical standard
Sigma-Aldrich
Quinidine, crystallized, ≥98.0% (dried material, NT)
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Quinine, suitable for fluorescence, anhydrous, ≥98.0% (dried material, NT)
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Pyridine, ACS reagent, ≥99.0%
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Pyridine, biotech. grade, ≥99.9%
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Pyridine, ReagentPlus®, ≥99%
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Pyridine, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.5% (GC)
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Pyridine, ReagentPlus®, ≥99%
Supelco
Pyridine, Pharmaceutical Secondary Standard; Certified Reference Material
Trolamine impurity A, European Pharmacopoeia (EP) Reference Standard
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Pyridine, anhydrous, 99.8%
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Benzimidazole, 98%
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Quinine, certified reference material, TraceCERT®
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