RESUMO
Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are under way to develop therapies that target essential biological processes in S. aureus. Antimicrobial photodynamic therapy is an effective alternative to antibiotics; therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photosensitizers. A near infrared photosensitizer was conjugated to human monoclonal antibodies (MAbs) that target the S. aureus iron-regulated surface determinant (Isd) heme acquisition proteins. In addition, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial photodynamic treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd MAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções dos Tecidos Moles , Infecções Estafilocócicas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureusRESUMO
CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 â« 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.
Assuntos
Aromatase/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Aldosterona/metabolismo , Aromatase/metabolismo , Citocromo P-450 CYP11B2/antagonistas & inibidores , Citocromo P-450 CYP11B2/metabolismo , Desenho de Fármacos , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Esteroide 11-beta-Hidroxilase/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC50 > 50 µM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Indóis/síntese química , Isoquinolinas/síntese química , Piridinas/síntese química , Animais , Aromatase/metabolismo , Células Cultivadas , Cricetinae , Humanos , Indóis/química , Indóis/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Fígado/enzimologia , Simulação de Acoplamento Molecular , Piridinas/química , Piridinas/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Beginning with a moderately potent PPARgamma agonist 9, a series of potent and highly subtype-selective PPARalpha agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.
Assuntos
Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/síntese química , PPAR alfa/agonistas , Animais , Cricetinae , Cães , Haplorrinos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Estrutura Molecular , PPAR alfa/genética , Ratos , Relação Estrutura-Atividade , Ativação TranscricionalRESUMO
Bile salt export pump (BSEP) is a major bile acid transporter in the liver. Mutations in BSEP result in progressive intrahepatic cholestasis, a severe liver disease that impairs bile flow and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and such inhibition and down-regulation may result in bile acid retention and intrahepatic cholestasis. In this study, we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocytes and HepG2 cells. We demonstrate that BSEP expression is dramatically regulated by ligands of the nuclear receptor farnesoid X receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression. Previous studies did not identify LCA as an FXR antagonist ligand in cells, but we show here that LCA is an FXR antagonist with partial agonist activity in cells. In an in vitro co-activator association assay, LCA decreased CDCA- and GW4064-induced FXR activation with an IC(50) of 1 microm. In HepG2 cells, LCA also effectively antagonized GW4064-enhanced FXR transactivation. These data suggest that the toxic and cholestatic effect of LCA in animals may result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potential therapeutic drugs for intrahepatic cholestasis.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isoxazóis/farmacologia , Ácido Litocólico/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Clonagem Molecular , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Escherichia coli/genética , Glutationa Transferase/metabolismo , Humanos , Oxigenases de Função Mista/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares , Proteínas Recombinantes de Fusão/metabolismo , Rifampina/farmacologia , Transcrição Gênica/efeitos dos fármacos , Transfecção , Células Tumorais CultivadasRESUMO
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Fatores de Transcrição/agonistas , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacocinética , Fatores de Transcrição/agonistas , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Camundongos , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologiaRESUMO
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.