CCR3 antagonists where the piperidine ring is replaced by a morpholine are exemplified by compounds 17 and 18 (63-64). Compound 17 Is a potent inhibitor in the CCR3 binding assay (IC50 = 4.1 nM). In ovalbumin-sensitized guinea pigs, compound 18 (CCR3 binding IC50 = 660 nM; 0.2-20 mg/kg, p.o.) produced inhibition of lung eoslnophilia and bronchial hyperreactivitiy (64).

A novel structural class comprising a pyrrolo-[3,4-c]pyrrolidine tether/linker is illustrated by compounds 19 and 20 (65). The selectivity of this series was evaluated for Inhibition of eotaxin-induced chemotaxis in murine pre-B cells transfected with CCR3 and in MCP 1-induced chemotaxis in THP-1 monocytes. In general, compounds where R = CH3 were selective for the CCR2 receptor and compounds where R = CI were selective for the CCR3 receptor. Analogs of 20 completely blocked the binding of eotaxin to the CCR3 receptor in murine pre-B cells transfected with CCR3 at 1 uM.

Urea analogs 21 and 22 that completely block eotaxin-induced chemotaxis at 10 uM concentrations, suppress type II collagen-induced arthritis in mice at 50 mg/kg s.c. and 20 mg/kg s.c., respectively (66). In ovalbumin-sensitized mice, compound 21 (50 mg/kg, i.p.) produced a reduction in bronchial hyperresponsiveness to injected acetyl choline and an approximate 50% reduction in BAL eosinophils.

20 R = CI


Was this article helpful?

0 0
Natural Arthritis Pain Remedies

Natural Arthritis Pain Remedies

It's time for a change. Finally A Way to Get Pain Relief for Your Arthritis Without Possibly Risking Your Health in the Process. You may not be aware of this, but taking prescription drugs to get relief for your Arthritis Pain is not the only solution. There are alternative pain relief treatments available.

Get My Free Ebook

Post a comment