RESUMO
Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.
Assuntos
Apolipoproteínas B/sangue , Proteínas de Transporte/antagonistas & inibidores , Colesterol/sangue , Fluorenos/farmacologia , Hiperlipoproteinemia Tipo II/sangue , Piperidinas/farmacologia , Triglicerídeos/sangue , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fluorenos/química , Fluorenos/farmacocinética , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipídeos/sangue , Lipoproteínas/sangue , Fígado/metabolismo , Camundongos , Piperidinas/química , Piperidinas/farmacocinética , Coelhos , Ratos , Triglicerídeos/metabolismo , Células Tumorais CultivadasAssuntos
Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Hipolipemiantes/farmacologia , Ácidos Sulfônicos/farmacologia , Animais , Colesterol/sangue , Cricetinae , Hipolipemiantes/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Conformação Molecular , Ratos , Ácidos Sulfônicos/químicaAssuntos
Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Hipolipemiantes/farmacologia , Pró-Fármacos/farmacologia , Ácidos Sulfônicos/farmacologia , Administração Oral , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Hipolipemiantes/síntese química , Hipolipemiantes/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/químicaRESUMO
Inhibitors of squalene synthase have the potential to be superior cholesterol-lowering agents. We previously disclosed that lipophilic 1,1-bisphosphonates I are potent squalene synthase inhibitors and orally active cholesterol-lowering agents in animal models (Ciosek, C. P., Jr.; et al. J. Biol. Chem. 1993, 268, 24832-24837). In this paper, we describe modifications to the bisphosphonate moiety, in an attempt to reduce the number of acidic functions contained in these inhibitors. Replacing one of the acidic groups with a methyl (II, R2 = CH3) results in potent inhibitors when paired with a close mimic of the naturally occurring farnesyl moiety (R1 = farnesylethyl) but not when paired with the shorter isoprene surrogates (R1 = geranylethyl or 4-biphenylpropyl). In contrast, all three corresponding bisphosphonates I are potent squalene synthase inhibitors. Inhibitory potency is recovered with the shorter isoprene surrogates when R2 is CH2OH or CH2OCH3. It is proposed that these R2 groups serve as hydrogen bond acceptors with the active site of the enzyme. The properties of these compounds as cholesterol biosynthesis inhibitors in rats are described, and synthetic routes to these and related compounds are detailed.
Assuntos
Difosfonatos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Hipolipemiantes/farmacologia , Animais , Difosfatos/química , Difosfonatos/química , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/enzimologia , Fosfatos de Poli-Isoprenil/química , RatosRESUMO
Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene at the final branchpoint of the cholesterol biosynthetic pathway. We report herein that isoprenyl 1,1-bisphosphonates and related analogs are potent inhibitors of rat microsomal squalene synthase (I50 = 0.7-32 nM). In addition, members of this family are potent inhibitors of cholesterol biosynthesis in rats on intravenous and oral dosing, as well as cholesterol lowering agents in rats and hamsters. Significant inhibition of cholesterol biosynthesis in rats by lovastatin occurs with a concomitant inhibition of dolichol and coenzyme-Q9 synthesis. In contrast, bisphosphonate 4 has no effect on dolichol and coenzyme-Q9 biosynthesis in rats under conditions where cholesterol biosynthesis is > 90% inhibited.