RESUMO
During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.
Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor TIE-2/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Área Sob a Curva , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HT29 , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Modelos Moleculares , Transplante de Neoplasias , RNA/biossíntese , RNA/genéticaRESUMO
The left ventricular hypertrophy (LVH) in response to pressure overload is an important risk factor in cardiac morbidity and mortality. To investigate the time course of histopathological alterations in the LVH in response to pressure overload, histopathological and immunohistochemical examination was performed using the aortic banding-induced mouse LVH model. Five-week-old male CD-1 mice were subjected to the inter-renal aortic banding. Major organs were sampled on 3, 10, 14, 21, 28 or 42 days after banding. Haematoxylin and eosin (H&E) staining, Masson's trichrome staining and immunohistochemistry for proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (aSMA), ICAM-1, type I collagen and CD31 was performed and microscopically examined. Three days after aortic banding, acute inflammatory changes, such as macrophages/neutrophil infiltration and vascular wall injury were observed on/around the coronary arteries/arterioles of both ventricles. Intense ICAM-1 immunostaining was observed on the endothelium of the coronary arteries/arterioles. After day 10, vascular wall thickening and perivascular fibrosis was induced on the coronary arteries/arterioles. Immunohistochemistry for aSMA and PCNA demonstrated the proliferation of vascular smooth muscle cells in the media. After day 28, minimal cardiomyocyte hypertrophy was observed at the light microscope level. In the inter-renal aortic banding LVH model, histopathological alterations in early phase were mainly observed on coronary arteries/arterioles. These early phase alterations were thought to be hypertension-related changes in the coronary vasculatures. The cardiomyocyte hypertrophy observed in later phase was minimal at the light microscope level. These evidences would facilitate the understanding of pathophysiology of pressure overload LVH.
