title: Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment.
abstract: Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. min_shu@merck.com
authors.forename: Min
authors.initials: M
authors.lastname: Shu
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Loebach
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Parker
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.forename: Lorraine
authors.initials: L
authors.lastname: Malkowitz
authors.forename: Martin S
authors.initials: MS
authors.lastname: Springer
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Gould
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Siciliano
authors.forename: Jerry Di
authors.initials: JD
authors.lastname: Salvo
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.forename: James V
authors.initials: JV
authors.lastname: Pivnichny
authors.forename: Gloria Y
authors.initials: GY
authors.lastname: Kwei
authors.forename: Anthony
authors.initials: A
authors.lastname: Carella
authors.forename: Gwen
authors.initials: G
authors.lastname: Carver
authors.forename: Karen
authors.initials: K
authors.lastname: Holmes
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Renee
authors.initials: R
authors.lastname: Danzeisen
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Joseph
authors.initials: J
authors.lastname: Kessler
authors.forename: Janet
authors.initials: J
authors.lastname: Lineberger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Emini
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles