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

C P Dorn; P E Finke; B Oates; R J Budhu; S G Mills; M MacCoss; L Malkowitz; M S Springer; B L Daugherty; S L Gould; J A DeMartino; S J Siciliano; A Carella; G Carver; K Holmes; R Danzeisen; D Hazuda; J Kessler; J Lineberger; M Miller; W A Schleif; E A Emini

doi:10.1016/s0960-894x(00)00637-5

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

Bioorg Med Chem Lett. 2001 Jan 22;11(2):259-64. doi: 10.1016/s0960-894x(00)00637-5.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.

PMID: 11206473
DOI: 10.1016/s0960-894x(00)00637-5

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.

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry
Anti-HIV Agents / metabolism
CCR5 Receptor Antagonists*
CHO Cells
Chemokine CCL4
Combinatorial Chemistry Techniques
Cricetinae
Humans
Inhibitory Concentration 50
Macrophage Inflammatory Proteins / metabolism
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / metabolism
Protein Binding
Receptors, CCR5 / genetics
Receptors, CCR5 / metabolism
Structure-Activity Relationship
Transfection

Substances

Anti-HIV Agents
CCR5 Receptor Antagonists
Chemokine CCL4
Macrophage Inflammatory Proteins
Piperidines
Receptors, CCR5