RESUMO
Age-related Macular Degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly in developed countries. Neovascular/exudative (wet) AMD is the aggressive form of AMD and can involve choroidal neovascularization and vascular leakage. Anti-vascular endothelial growth factor (anti-VEGF) medications have significantly improved treatment of wet-AMD. However, only approximately 40% of patients obtain full benefit from anti-VEGF therapy and the medications are given by intravitreal injection. Axitinib, a small molecule multi-receptor tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, is taken orally and inhibits VEGF activity by blocking VEGF receptors. Axitinib also has the advantage of blocking platelet derived growth factor (PDGF) receptors which play a role in neovascularization. Using in vitro human retinal microvascular endothelial cells (HRMVECs), human brain vascular pericytes (HBVRs), 3D co-culture vessel sprout assay, and in vivo laser induced rat choroidal neovascularization (CNV) models, the effect of axitinib on neovascularization was evaluated. Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD. Additionally, axitinib showed good efficacy at a low dose (0.875 mg/day) in laser-induced CNV model in rats. In conclusion our data shows that axitinib, an inhibitor of VEGF and PDGF-B pathways may be useful in ameliorating wet-AMD therapy.
Assuntos
Neovascularização de Coroide/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Animais , Axitinibe , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Angiofluoresceinografia , Humanos , Imidazóis/farmacologia , Imuno-Histoquímica , Indazóis/farmacologia , Injeções Intravítreas , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pericitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , RatosRESUMO
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pirazóis/uso terapêutico , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/imunologia , Doença Crônica , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.