RESUMO
We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high antiviral activity against wild-type (WT) and the T174I mutant (EC50 (WT) = 4.6 nM, EC50 (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high antiviral activity.
Assuntos
Inibidores de Integrase de HIV , Integrase de HIV , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antivirais/farmacologia , Derivados de Benzeno/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Derivados de Benzeno/metabolismo , Derivados de Benzeno/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for µ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for µ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood-brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.
Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Naltrexona/análogos & derivados , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Naltrexona/farmacologia , Ratos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND/AIM: Matrix metalloproteinases (MMPs) play pivotal roles in extracellular matrix turnover and are involved in chronic kidney disease. The renoprotective action of a synthetic MMP inhibitor, compound A, was investigated in chronic nephritis. METHODS: Nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. The effects of compound A on proteinuria, blood urea nitrogen, and matrix-related gene expressions were evaluated. Collagen accumulation, as assessed by periodic acid-Schiff staining and hydroxyproline content, was determined. The integrity of glomerular epithelial cells and glomerular basement membrane was evaluated with desmin immunohistochemistry and electron microscopic detection of anionic charge sites, respectively. RESULTS: Treatment with compound A notably attenuated proteinuria, ameliorated blood urea nitrogen, and prevented glomerulosclerosis. Gene upregulation of collagen and transforming growth factor ß1 in the cortex was prevented in the treated animals. Glomerular epithelial cell injury was milder, and glomerular basement membrane anionic sites were protected with the treatment. CONCLUSION: A novel MMP inhibitor, compound A, exerts protective effects in progressive glomerulonephritis. Compound A ameliorates various aspects of renal injuries and may have therapeutic potential toward kidney diseases.
RESUMO
L-Ribose was synthesized by a simple four-step method with overall yield of 76.3% from a protected L-arabinose derivative, which is a compatible intermediate for the synthesis of L-deoxyribose. The key step of this strategy is the Swern oxidation and subsequent stereoselective reduction accompanied by inversion of the 2-hydroxy group of protected L-arabinose.
Assuntos
Arabinose/química , Ribose/síntese química , Desoxirribose/síntese química , Desoxirribose/química , Nucleosídeos/síntese química , Nucleosídeos/química , Ribose/químicaRESUMO
We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively combine the aromatic rings. The highly efficient and practical production of this important natural product offers promise for the development of a new type of antiallergic drug.
RESUMO
Regioselective halogenations and Suzuki reactions ensure proper linkage of the aromatic rings in two total syntheses of terprenin (1). Both routes make it possible to prepare 1 efficiently and in large quantity.