Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis.

Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.

Pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor lumiracoxib in the lipopolysaccharide-stimulated rat air pouch model.

PURPOSE: To investigate the pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor, lumiracoxib, in the rat air pouch. METHODS: Air pouches were injected with lipopolysaccharide to stimulate prostaglandin E2 (PGE2) production 1h after lumiracoxib treatment. Pouch fluid samples were collected 6 or 24 h after lumiracoxib administration to measure PGE2 levels. Lumiracoxib concentrations in pouch fluid and plasma were measured by mass spectrometry. RESULTS: Oral administration of lumiracoxib resulted in dose-dependent inhibition of PGE2 production 6 and 24 h post-dose. The estimated ED50 values for inhibition of PGE2 production were 0.1 and 2.0 mg/kg at 6 and 24 h, respectively. Lumiracoxib concentrations in plasma and pouch fluid increased in proportion to dose. There was a strong positive correlation between lumiracoxib concentrations in plasma and pouch fluid compartments. Lumiracoxib concentrations were higher in plasma than in pouch fluid 6 h post-dose, but at 24 h post-dose, pouch fluid concentrations were > or =4-fold greater than plasma concentrations. CONCLUSIONS: Lumiracoxib readily enters the air pouch and persists in this extravascular compartment for a longer period of time than in plasma. This distribution profile may contribute to the ability of lumiracoxib to inhibit PGE2 production up to 24 h after dosing.

Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2.

1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.