title: Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure-activity relationships for substituted 2-Aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes.
abstract: (2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. paul_finke@merck.com
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: L C
authors.initials: LC
authors.lastname: Meurer
authors.forename: B
authors.initials: B
authors.lastname: Oates
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: L
authors.initials: L
authors.lastname: Malkowitz
authors.forename: M S
authors.initials: MS
authors.lastname: Springer
authors.forename: B L
authors.initials: BL
authors.lastname: Daugherty
authors.forename: S L
authors.initials: SL
authors.lastname: Gould
authors.forename: J A
authors.initials: JA
authors.lastname: DeMartino
authors.forename: S J
authors.initials: SJ
authors.lastname: Siciliano
authors.forename: A
authors.initials: A
authors.lastname: Carella
authors.forename: G
authors.initials: G
authors.lastname: Carver
authors.forename: K
authors.initials: K
authors.lastname: Holmes
authors.forename: R
authors.initials: R
authors.lastname: Danzeisen
authors.forename: D
authors.initials: D
authors.lastname: Hazuda
authors.forename: J
authors.initials: J
authors.lastname: Kessler
authors.forename: J
authors.initials: J
authors.lastname: Lineberger
authors.forename: M
authors.initials: M
authors.lastname: Miller
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002073:Butanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002082:Butylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054407:Chemokine CCL4; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
chemical_list: D019380:Anti-HIV Agents; D002073:Butanes; D002082:Butylamines; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010880:Piperidines; D019713:Receptors, CCR5; D013449:Sulfonamides