Medicinal chemical properties of successful central nervous system drugs

Abstract

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.

FIG. 1.

Molecular dynamics simulations of acyclovir and diazepam passive transport through a DMPC membrane. (Courtesy of Prof. A. J. Hopfinger, University of Illinois-Chicago, Chicago, IL. Copyright © 2005, The Chem21 Group, Inc., Chicago, IL. All rights reserved.). Top: Side view (A) and top view (B) of the structure for the model DMPC membrane-acycloviar complex after 200 psec of MDS. Acyclovir has low (slow) cellular permeability Bottom: Side view (A) and top view (B) of the structure for the model DMPC membrane-diazepam complex after 200 psec of MDS. Diazepam has high (rapid) cellular permeability.