title: Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile.
abstract: We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kazmierski@gsk.com
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Don L
authors.initials: DL
authors.lastname: Anderson
authors.forename: Christopher
authors.initials: C
authors.lastname: Aquino
authors.forename: Brian A
authors.initials: BA
authors.lastname: Chauder
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Robert
authors.initials: R
authors.lastname: Ferris
authors.forename: Terrence
authors.initials: T
authors.lastname: Kenakin
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Koble
authors.forename: Dan G
authors.initials: DG
authors.lastname: Lang
authors.forename: Maggie S
authors.initials: MS
authors.lastname: McIntyre
authors.forename: Jennifer
authors.initials: J
authors.lastname: Peckham
authors.forename: Christian
authors.initials: C
authors.lastname: Watson
authors.forename: Pat
authors.initials: P
authors.lastname: Wheelan
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wire
authors.forename: Angilique
authors.initials: A
authors.lastname: Svolto
authors.forename: Michael
authors.initials: M
authors.lastname: Youngman
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D000882:Haplorhini; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D014326:Tropanes
chemical_list: D019380:Anti-HIV Agents; D053961:Azabicyclo Compounds; D001562:Benzimidazoles; D065100:CCR5 Receptor Antagonists; D051638:Ether-A-Go-Go Potassium Channels; C560275:GSK 163929; D010880:Piperidines; D013449:Sulfonamides; D014326:Tropanes