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
The total synthesis of polygalolideâ A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier-type C-glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D-glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C-glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6-collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton-McCombie reaction. The construction of the six-membered ether and the γ-lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolideâ A.