title: Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains.
abstract: Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. dongming_shen@merck.com
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.forename: Min
authors.initials: M
authors.lastname: Shu
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
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: 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*; D065100:CCR5 Receptor Antagonists; D002455:Cell Division / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; 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