Abstract
The tissue distribution of a drug can have significant impact on both its efficacy and safety. As a consequence, selective tissue targeting has become an attractive approach for optimizing the window between efficacy and safety for drug targets that are ubiquitously expressed and important in key physiological processes. Given the liver’s key role in metabolic regulation and the fact that it is the principal tissue affected by diseases such as hepatitis B and C viruses as well as hepatocellular carcinoma, designing drugs with hepatoselective distribution profiles is an important strategy in developing safe cardiovascular, metabolic, antiviral and oncology drug candidates.
In this paper, we analyze a diverse set of compounds from four different projects within Pfizer that specifically pursued liver targeting strategies. A number of key in vitro and in vivo ADME endpoints were collected including in vivo tissue exposure, oral bioavailability, clearance in preclinical species and in vitro hepatic OATP uptake, in vitro rat liver microsomal stability, permeability, solubility, logD, and others. From this analysis, we determined a set of general structureliver- selectivity guides for designing orally bioavailable, liver-targeted candidates using liver specific OATP transporters. The guidelines have been formulated using straightforward molecular descriptors and in vitro properties that medicinal chemists routinely optimize.
Our analysis emphasizes the need to focus on a chemical space with balanced lipophilicity, high aqueous solubility and low passive permeability in order to achieve the desired hepatoselectivity while maintaining fraction absorbed.
Keywords: Clearance, Fraction of absorbed, Liver targeting, Liver selectivity, Lipophilicity, Organic anion-transporting polypeptide (OATP), Passive permeability, Tissue distribution, tissUe exposure, Tissue selectivity.
Current Topics in Medicinal Chemistry
Title:Medicinal Chemistry Design Principles for Liver Targeting Through OATP Transporters
Volume: 13 Issue: 7
Author(s): Meihua Tu, Alan M. Mathiowetz, Jeffrey A. Pfefferkorn, Kimberly O. Cameron, Robert L. Dow, John Litchfield, Li Di, Bo Feng and Spiros Liras
Affiliation:
Keywords: Clearance, Fraction of absorbed, Liver targeting, Liver selectivity, Lipophilicity, Organic anion-transporting polypeptide (OATP), Passive permeability, Tissue distribution, tissUe exposure, Tissue selectivity.
Abstract: The tissue distribution of a drug can have significant impact on both its efficacy and safety. As a consequence, selective tissue targeting has become an attractive approach for optimizing the window between efficacy and safety for drug targets that are ubiquitously expressed and important in key physiological processes. Given the liver’s key role in metabolic regulation and the fact that it is the principal tissue affected by diseases such as hepatitis B and C viruses as well as hepatocellular carcinoma, designing drugs with hepatoselective distribution profiles is an important strategy in developing safe cardiovascular, metabolic, antiviral and oncology drug candidates.
In this paper, we analyze a diverse set of compounds from four different projects within Pfizer that specifically pursued liver targeting strategies. A number of key in vitro and in vivo ADME endpoints were collected including in vivo tissue exposure, oral bioavailability, clearance in preclinical species and in vitro hepatic OATP uptake, in vitro rat liver microsomal stability, permeability, solubility, logD, and others. From this analysis, we determined a set of general structureliver- selectivity guides for designing orally bioavailable, liver-targeted candidates using liver specific OATP transporters. The guidelines have been formulated using straightforward molecular descriptors and in vitro properties that medicinal chemists routinely optimize.
Our analysis emphasizes the need to focus on a chemical space with balanced lipophilicity, high aqueous solubility and low passive permeability in order to achieve the desired hepatoselectivity while maintaining fraction absorbed.
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Cite this article as:
Tu Meihua, Mathiowetz Alan M., Pfefferkorn Jeffrey A., Cameron Kimberly O., Dow Robert L., Litchfield John, Di Li, Feng Bo and Liras Spiros, Medicinal Chemistry Design Principles for Liver Targeting Through OATP Transporters, Current Topics in Medicinal Chemistry 2013; 13 (7) . https://dx.doi.org/10.2174/1568026611313070008
DOI https://dx.doi.org/10.2174/1568026611313070008 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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