RESUMEN
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.
Asunto(s)
Pirrolidinonas/química , Receptores de Formil Péptido/agonistas , Receptores de Lipoxina/agonistas , Animales , Quimiotaxis/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Células HEK293 , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/prevención & control , Humanos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Neutrófilos/citología , Neutrófilos/fisiología , Fagocitosis/efectos de los fármacos , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico , Receptores de Formil Péptido/genética , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/genética , Receptores de Lipoxina/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis. METHODS: BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis. In vivo, BMS-189453 was evaluated in 2 animal models of arthritis: collagen induced arthritis (CIA) in mice and streptococcal cell wall induced arthritis (SCWA) in rats. Clinical scores for arthritis were recorded weekly. At the end of each study, limbs were evaluated histologically. In CIA, these results were correlated with mRNA levels for collagenase-3 (MMP-13) and stromelysin-1 (MMP-3) as determined by Northern blot. RESULTS: BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Histological evaluation of the joints from animals in both models confirmed this result. Analysis of mRNA from the CIA paws showed that BMS-189453 prevented the overexpression of MMP-13 and MMP-3 in arthritic joints. CONCLUSION: Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression. This is the first study to show the clinical potential of RAR antagonists in arthritis.