RESUMO
In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Elongases de Ácidos Graxos/antagonistas & inibidores , Pirimidinas/farmacologia , Administração Oral , Adrenoleucodistrofia/tratamento farmacológico , Animais , Disponibilidade Biológica , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Éteres/química , Células HEK293 , Humanos , Macaca fascicularis , Camundongos , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , RatosRESUMO
Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27âa highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Elongases de Ácidos Graxos/administração & dosagem , Pirazóis/farmacologia , Adrenoleucodistrofia/tratamento farmacológico , Adrenoleucodistrofia/patologia , Amidas/química , Animais , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The synthesis consists of 14 longest linear steps, with 19% overall yield.
RESUMO
Four corners: The syntheses of four key building blocks for the total synthesis of norhalichondrin B (see structure) are described. The assembly of these subunits into the natural product is also reported. Key features of the synthesis are the use of the Achmatowicz oxidation/ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans.
Assuntos
Furanos/síntese química , Piranos/síntese química , Furanos/química , Hidrogenação , Piranos/químicaRESUMO
A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other 8 stereocenters.
RESUMO
A synthesis of highly functionalized pyranopyrans based on an Achmatowicz oxidation followed by a remarkably diastereoselective Kishi reduction is described in the context of studies directed toward norhalichondrin B.
Assuntos
Carbono/química , Furanos/química , Piranos/síntese química , Furanos/síntese química , Estrutura Molecular , Oxirredução , Piranos/químicaAssuntos
Antineoplásicos/síntese química , Éteres Cíclicos/síntese química , Furanos/síntese química , Cetonas/síntese química , Neoplasias/tratamento farmacológico , Piranos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Éteres Cíclicos/química , Éteres Cíclicos/farmacologia , Furanos/química , Furanos/farmacologia , Humanos , Cetonas/química , Cetonas/farmacologia , Macrolídeos , Piranos/química , Piranos/farmacologia , Relação Estrutura-AtividadeRESUMO
Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products. Newly isolated mycolactones correspond to the "oxidized forms" of mycolactone A/B, the causative toxin of Buruli ulcer, isolated from Mycobacterium ulcerans.
Assuntos
Macrolídeos/síntese química , Mycobacterium ulcerans/química , Úlcera de Buruli/etiologia , Cromatografia Líquida de Alta Pressão , Macrolídeos/química , Estrutura MolecularRESUMO
A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.