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

Abstract

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 1alpha (MIP-1alpha) 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 IC(50) 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.

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…Several CCR1 antagonists have been clinically assessed in the context of inflammatory diseases without significant effects, presumably due to redundancy of signaling in the chemokine family and suboptimal pharmacokinetic properties of the inhibitors used [105]. Novel agents with improved potency and physical/chemical properties are currently under evaluation [106,107].…”

Role of platelets in neuroinflammation: a wide-angle perspective

“…That leukocyte infiltration is driven by CCL5 gained further support by the clinical and laboratory observations of Jalosinski et al [78]. At least one novel drug is in the pipeline which targets CCR1 (another receptor for CCL5) for therapy of MS and other inflammatory disorders [79]. Similar findings on the importance of RANTES are seen in EAE models [80-83].…”

Oxidation Potentials of N‐Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity

“…[27,28] The second component was the chlorinated pyridine ring 13, which was nitrated by using hot nitrosulfuric acid to obtain 14. [27,28] The second component was the chlorinated pyridine ring 13, which was nitrated by using hot nitrosulfuric acid to obtain 14.…”