title: The discovery of tropane-derived CCR5 receptor antagonists.
abstract: 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.
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Armour
authors.forename: Marcel J
authors.initials: MJ
authors.lastname: de Groot
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Blanda L C
authors.initials: BL
authors.lastname: Stammen
authors.forename: Anthony
authors.initials: A
authors.lastname: Wood
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Catherine
authors.initials: C
authors.lastname: Burt
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010880:Piperidines; D019713:Receptors, CCR5; D014326:Tropanes; C032727:piperidine