Medicinal chemical properties of successful central nervous system drugs

Abstract

Summary:Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties.

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

“…Taken collectively, the combination of a low f u and an affinity for the lipophilic environment of the brain favor accumulation of efavirenz in the CNS. Lipophilicity has been shown to be a significant factor in uptake of drugs into the brain (25). Lipophilicity, but not plasma protein binding, was shown to correlate with uptake of benzodiazepines, for example, into the brain.…”

In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer’s Disease

“…For example, Liothyronine (a synthetic form of the thyroid hormone) has previously been used to treat hyperthyroidism and myxoedema, as well as in an augmentation strategy in treating major depressive disorder in combination with antidepressants. 22 However, there are links to thyroid replacement therapy and the advancement of AD symptoms, therefore this drug may not be the most promising starting point for a potential therapeutic for AD. 23 Another former FDA approved drug identified in our screen was Alosetron.HCl (Lotronex, GSK).…”

The First CNS-Active Carborane: A Novel P2X7 Receptor Antagonist with Antidepressant Activity

“…20 The three benzamides 1, 3, and 4, which showed no antidepressant behavior in the FST, were shown to have log D 7.4 values much greater than the range reported for successful CNS drugs (cLogP < 3). 21 These values indicate that a high lipophilicity may be inhibiting BBB penetration, which consequently eliminated their efficacy in the FST. Interestingly, substituting adamantane for closo-1,2-carborane in the benzamides does not increase the lipophilicity of the drug as previously reported in literature.…”