PlumX Metrics
Embed PlumX Metrics

Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 52, Issue: 5, Page: 1295-1301
2009
  • 25
    Citations
  • 0
    Usage
  • 25
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

Article Description

Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1a (MIP-1a) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC50 of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability. © 2009 American Chemical Society.

Bibliographic Details

Merritt, J Robert; Liu, Jinqi; Quadros, Elizabeth; Morris, Michelle L; Liu, Ruiyan; Zhang, Rui; Jacob, Biji; Postelnek, Jennifer; Hicks, Catherine M; Chen, Weiqing; Kimble, Earl F; Rogers, W Lynn; O'Brien, Linda; White, Nicole; Desai, Hema; Bansal, Shalini; King, George; Ohlmeyer, Michael J; Appell, Kenneth C; Webb, Maria L

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

Provide Feedback

Have ideas for a new metric? Would you like to see something else here?Let us know