Novel Pyrrolidine Ureas as C-C Chemokine Receptor 1 (CCR1) Antagonists

被引：22

作者：

Merritt, J. Robert ^{[1
]}

Liu, Jinqi ^{[1
]}

Quadros, Elizabeth ^{[1
]}

Morris, Michelle L. ^{[1
]}

Liu, Ruiyan ^{[1
]}

Zhang, Rui ^{[1
]}

Jacob, Biji ^{[1
]}

Postelnek, Jennifer ^{[1
]}

Hicks, Catherine M. ^{[1
]}

Chen, Weiqing ^{[1
]}

Kimble, Earl F. ^{[1
]}

Rogers, W. Lynn ^{[1
]}

O'Brien, Linda ^{[1
]}

White, Nicole ^{[1
]}

Desai, Hema ^{[1
]}

Bansal, Shalini ^{[1
]}

King, George ^{[1
]}

Ohlmeyer, Michael J. ^{[1
]}

Appell, Kenneth C. ^{[1
]}

Webb, Maria L. ^{[1
]}

机构：

[1] Pharmacopeia Inc, Cranbury, NJ 08512 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 05期

关键词：

DISEASE; RANTES; PATHOGENESIS; ARTHRITIS;

D O I：

10.1021/jm801416q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 1 alpha (MIP-1 alpha) 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.

引用

页码：1295 / 1301

页数：7

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