title: Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1: discovery and initial structure-activity relationships for 1 -amino-2-phenyl-4-(piperidin-1-yl)butanes.
abstract: Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Dorn
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: B
authors.initials: B
authors.lastname: Oates
authors.forename: R J
authors.initials: RJ
authors.lastname: Budhu
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; 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; D014162:Transfection
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010880:Piperidines; D019713:Receptors, CCR5