October 30 - November 2, 2006, AAPS 2006, San Antonio, TX, USA

Improving Solubility in Drug Candidates—A Novel Software Aided Approach to Lead Optimization

Sanjivanjit K. Bhal, Karim Kassam, and Greg Pearl

Abstract

Purpose: To demonstrate how critical inter-related molecular properties can be improved in drug candidates using a software-aided approach to structural modification in the lead optimization process.
Method: Through consideration of critical physicochemical properties of a substance, either or both pK_a and logP (or logD) can be modified to influence intrinsic solubility or solubility at a relevant pH. A software tool that combines physicochemical property predictors with a database of 30,000 drug-like substituents was used to effect modifications for various physicochemical properties.
Results: We will discuss case studies that illustrate how inter-related physical properties such as pK_a, logP, and logD can be modified to improve physical properties, for example, solubility (hence bioavailability). These structural modifications are carried out either through subtle alterations such as heterocyclic replacement, or functional group interchange, or more drastic changes such as addition of substituents.
Conclusion: Balancing physical properties with efficacy is critical to produce viable drug candidates. These complex properties, however, can be very difficult to adjust. Software can aid lead optimization by suggesting structural modifications based on improving molecular properties. This approach allows the chemist to quickly generate a diverse set of analogs for synthetic evaluation whilst retaining the pharmacaphore.

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