1.
Bioorg Med Chem Lett
; 14(4): 1039-42, 2004 Feb 23.
Artigo
em Inglês
| MEDLINE
| ID: mdl-15013019
RESUMO
The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).
Assuntos
Benzoína/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Administração Oral , Animais , Benzoína/análogos & derivados , Benzoína/síntese química , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Insetos , Camundongos , Camundongos Knockout , Modelos Animais , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett
; 14(4): 1043-8, 2004 Feb 23.
Artigo
em Inglês
| MEDLINE
| ID: mdl-15013020
RESUMO
A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.