Abstract
Permeability is important in governing the ability of drug substances to transport across gastrointestinal membrane and also crucial for proper drug distribution to pharmacological target organs and cells, and is therefore frequently utilized in drug discovery and development. In this report, we have performed a systematic analysis, using principal component analysis on the historically measured permeability data from in-house Caco-2 and parallel artificial membrane permeability assays on discovery new chemical entities from multiple projects. This work allows for establishment of a permeability diagnosis model by purposefully identifying most influencing physicochemical properties of the permeability issues, including polarity-lipophilicity line contributed primarily by polar surface area and LogP, number of rotation bond, fractional ionization at neutral pH and efflux ratio. A number of cases were also shown to demonstrate the applicability of the current model. The analysis of the model over internal drug discovery compounds exhibited promising diagnostic and predictive power of the model. The advantages and limitation of the model as well as the integral strategy to apply it in drug discovery to guide projects for permeability-related optimization were also presented.
Keywords: Permeability diagnosis, ADME, oral absorption, gastrointestinal permeability, transporter, Caco-2 and PAMPA.
Current Topics in Medicinal Chemistry
Title:Permeability Diagnosis Model in Drug Discovery: A Diagnostic Tool to Identify the Most Influencing Properties for Gastrointestinal Permeability
Volume: 13 Issue: 11
Author(s): Jianling Wang and Suzanne Skolnik
Affiliation:
Keywords: Permeability diagnosis, ADME, oral absorption, gastrointestinal permeability, transporter, Caco-2 and PAMPA.
Abstract: Permeability is important in governing the ability of drug substances to transport across gastrointestinal membrane and also crucial for proper drug distribution to pharmacological target organs and cells, and is therefore frequently utilized in drug discovery and development. In this report, we have performed a systematic analysis, using principal component analysis on the historically measured permeability data from in-house Caco-2 and parallel artificial membrane permeability assays on discovery new chemical entities from multiple projects. This work allows for establishment of a permeability diagnosis model by purposefully identifying most influencing physicochemical properties of the permeability issues, including polarity-lipophilicity line contributed primarily by polar surface area and LogP, number of rotation bond, fractional ionization at neutral pH and efflux ratio. A number of cases were also shown to demonstrate the applicability of the current model. The analysis of the model over internal drug discovery compounds exhibited promising diagnostic and predictive power of the model. The advantages and limitation of the model as well as the integral strategy to apply it in drug discovery to guide projects for permeability-related optimization were also presented.
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Cite this article as:
Wang Jianling and Skolnik Suzanne, Permeability Diagnosis Model in Drug Discovery: A Diagnostic Tool to Identify the Most Influencing Properties for Gastrointestinal Permeability, Current Topics in Medicinal Chemistry 2013; 13 (11) . https://dx.doi.org/10.2174/15680266113139990035
DOI https://dx.doi.org/10.2174/15680266113139990035 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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