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The Discovery of Tropane‐derived CCR5 Receptor Antagonists
Author(s) -
Armour Duncan R.,
De Groot Marcel J.,
Price David A.,
Stammen Blanda L. C.,
Wood Anthony,
Perros Manos,
Burt Catherine
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00376.x
Subject(s) - tropane , piperidine , ccr5 receptor antagonist , stereochemistry , moiety , chemistry , antagonist , herg , pharmacology , receptor , biology , biochemistry , potassium channel , biophysics , chemokine , chemokine receptor
The development of compound 1, a piperidine‐based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane‐derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad‐spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a‐go‐go‐related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.