RESUMO
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Imidazolinas/síntese química , Imidazolinas/química , Imidazolinas/farmacologia , Modelos Moleculares , Relação Estrutura-Atividade , Tiazóis/síntese químicaRESUMO
DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.
Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Inibidores do Citocromo P-450 CYP2D6 , Compostos de Fenilureia/química , Piperidinas/química , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Compostos de Benzil/síntese química , Bioensaio , Células Cultivadas , Humanos , Camundongos , Pan troglodytes , Compostos de Fenilureia/farmacologia , Piperidinas/síntese química , Receptores CCR3 , Relação Estrutura-AtividadeRESUMO
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
Assuntos
Dipeptídeos/síntese química , Fosfotirosina/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Tiazóis/síntese química , Cristalografia por Raios X , Dipeptídeos/química , Desenho de Fármacos , Modelos Moleculares , Mimetismo Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Relação Quantitativa Estrutura-Atividade , Estereoisomerismo , Tiazóis/químicaRESUMO
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.