August 7 - 10, 2006, DDT 2006, Boston, MA, USA

Lead Optimization to Reduce Blood Brain Barrier Penetration - a Novel Software-Aided Approach

Sanjivanjit K. Bhal and Karim Kassam

Abstract

At the heart of every lead optimization exercise lies the challenge of relating chemical structure to changes in molecular properties. Potency is of utmost importance in this process, but at the same time, the chemist seeks to optimize other parameters such as pharmacokinetics and selectivity. In-vivo activity of a drug relies heavily on its ability to cross many biological barriers (penetration through the gastro-intestinal tract, first pass clearance through the liver) to reach intended sites of action, and is greatly influenced by the physicochemical properties of the compound (logP, logD, pK_a, aqueous solubility, etc.). Penetration through the blood brain barrier (BBB) is an example of a biological barrier that must be optimized for good penetration in therapeutics targeting the central nervous system, and minimized in compounds targeting other therapeutic areas to avoid side-effects. Using a software tool that combines physicochemical property predictors with a critically evaluated database of "drug-like" substituents, we illustrate a real-life lead optimization case study, the optimization of logP for 2-(2-dimethoxyphenyl)-1H-imidazo[4,5-b]pyridine to reduce BBB penetration.

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Relevant Product: ACD/Structure Design Suite

Relevant Solutions: MedChem, Agrochemical Research