Intramolecular Distribution of Hydrophobicity Influences Pharmacological Activity of Propafenone-type MDR Modulators

Lipophilicity is one of the major determining physicochemical descriptors for P‐glycoprotein (P‐gp) inhibitory activity. Recently, Pajeva and Wiese showed that in case of P‐gp interaction, lipophilicity may be regarded as space‐directed property. In the present study, a series of propafenone‐type P‐...

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Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 2004-06, Vol.337 (6), p.328-334
Main Authors: Pleban, Karin, Hoffer, Claudia, Kopp, Stephan, Peer, Michael, Chiba, Peter, Ecker, Gerhard F.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry
Biological and medical sciences
Cell Line, Tumor
Drug Design
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm
General aspects
Humans
Hydrophobic and Hydrophilic Interactions
Hydrophobicity distribution
Linear Models
Medical sciences
Multidrug resistance
P-Glycoprotein
Pharmacology. Drug treatments
Propafenone
Propafenone - analogs & derivatives
Propafenone - chemical synthesis
Propafenone - chemistry
Propafenone - pharmacology
Quantitative Structure-Activity Relationship
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Summary:Lipophilicity is one of the major determining physicochemical descriptors for P‐glycoprotein (P‐gp) inhibitory activity. Recently, Pajeva and Wiese showed that in case of P‐gp interaction, lipophilicity may be regarded as space‐directed property. In the present study, a series of propafenone‐type P‐gp inhibitors with systematically varying hydrophobicity distribution within the molecules were synthesised and pharmacologically tested. QSAR studies on the basis of multiple linear regression analysis showed that with increasing lipophilicity of the substituents on the amine moiety, the statistical significance of the indicator variables, denoting the substitution pattern on the central aromatic ring system, also increases. This indicates that the distribution of hydrophobicity within the molecules influences the mode of interaction with P‐gp.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.200300862