RESUMO
Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
Assuntos
Antivirais/síntese química , Inibidores da Protease de HIV/síntese química , HIV-1/efeitos dos fármacos , Indanos/síntese química , Piperazinas/síntese química , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Bovinos , Técnicas de Cultura de Células , Cães , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , Haplorrinos , Humanos , Indanos/química , Indanos/farmacocinética , Indanos/farmacologia , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Cálculos Urinários/induzido quimicamente , Cálculos Urinários/urinaRESUMO
Inositol 1,4,5-trisphosphate (InsP3) is a ubiquitous second messenger in eukaryotic cells that triggers Ca2+ release from intracellular stores. Three types of InsP3 receptors have been identified in mammals. The three receptor types are encoded by homologous genes and are structurally similar, suggesting two alternative hypotheses about the biological significance of multiple InsP3 receptors: (a) the different InsP3 receptors could have similar functions as InsP3-gated Ca2+ channels, and the presence of multiple genes could then serve as a mechanism to allow tissue-specific differential expression of receptors; or (b) the different receptors are co-expressed in cells but have distinct biological roles in these cells. To test these hypothesis, we have investigated the similarities and differences between the expression, alternative splicing, and ligand binding of different receptors. Our results demonstrate co-expression of different InsP3 receptors in almost all tissues and cell lines tested. Although all receptor types exhibit a similar specificity for inositol phosphates, the different receptors have different affinities for InsP3, with a relative order of affinities of type II > type I > type III. These findings suggest that the presence of multiple InsP3-sensitive Ca2+ pools with differential responsiveness to InsP3 may be a general property of all cells mediated by the presence of multiple types of InsP3 receptors.