Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Lead Optimization: Process to Design Preclinical Candidates

L.A. Gómez-Casajús

Department of Screening and Lead Optimization, Grupo Uriach

A lead is a compound that interacts with a target with sufficient potency and selectivity to warrant further chemical optimization to achieve a preclinical candidate. Lead optimization is, therefore, the complex, multi-step process of modifying the chemical structure of a compound to improve its drug characteristics and produce a preclinical drug candidate. In the past, drug design efforts were only focused on the optimization of affinity and selectivity for the target and demonstration of efficacy in animal models. However, new candidates currently need to demonstrate that they will have a good pharmacokinetic, metabolic and toxicity profile as well.

The design of new drugs requires that multiple properties be simultaneously optimized. A number of in vitro assays have been developed over the past decade to rapidly predict human pharmacokinetics and toxicity. Companies can now predict potential ADMET properties (absorption, distribution, metabolism, excretion and toxicity) with a similar efficacy to when they test pharmacological potency. During this stage of the drug discovery process, researchers must focus on a number of drug-like parameters including: permeability, metabolic stability, lipophilicity, solubility, plasma-protein binding, CYP450 interactions, pKa, PK/PD, etc.

Many efforts are underway to make lead optimization less time-consuming and more linear, as well as to bring down the cost of drug discovery and development. The major trend in lead optimization is the different strategies to accelerate the process, such as in silico and high-throughput in vitro approaches. Computational methods can be applied to chemical structures to predict ADMET properties even before the compound is synthesized so that only favorable compounds need be synthesized for screening. Whole cells are also increasingly being used in high-content screening mode to provide selectivity information along with other valuable data concerning the effects of compounds on cell function. New approaches for predicting cytotoxicity, blood brain barrier permeability and active transports in the early stages of drug discovery have also been developed.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com