Approach to Quick Lead Optimization Including Physicochemical and ADME Profiling

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July 21, 2011

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  • In recent years the pharmaceutical and biotechnology industries have made concerted efforts to focus on the quality of compounds produced in discovery rather than quantity. Lead optimization efforts are guided by a combination of factors, such as potency, ease of synthesis, specific constrains of the interaction with the target, as well as lead’s toxicity and ADME properties. Balancing numerous inter-related molecular properties (such as solubility and permeability) can be a significant challenge and quite often understanding the effect of individual properties and the relationship between property values and molecular structure is insufficient. Software tools that help address these concerns are of considerable value for medicinal chemists. A case study illustrates how inter-related physicochemical properties (LogP, hydrogen bonding), can be modified to improve ADME properties such as drug delivery across the blood brain barrier, using a new software tool ACD/Structure Design Suite that combines property predictors with a critically evaluated database of biologically-relevant substituents. Structural modifications are achieved through functional group interchange, heterocyclic group replacement, or addition of substituents while preserving an identified pharmacophore. The proposed modifications allow reducing the number of analogues that need to be synthesized to achieve optimal exposure at the site of action.

    Drug Discovery

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