RESUMO
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/farmacologia , Piridonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Concentração Inibidora 50 , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efeitos dos fármacos , Piridonas/química , Piridonas/farmacocinética , Ratos , Ratos WistarRESUMO
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Compostos Macrocíclicos/química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Sítios de Ligação , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Transplante HeterólogoRESUMO
As a result of an economically challenging environment within the pharmaceutical industry, pharmaceutical companies and their departments must increase productivity and cut costs to stay in line with the market. Discovery-led departments such as the medicinal chemistry and lead optimization groups focus on synthesizing large varieties of compounds in minimal amounts, while the chemical development groups must then deliver a few chosen leads employing an optimized synthesis method and using multi-kilogram quantities of material. A research group at the discovery-development interface has the task of medium-scale synthesis which is important in the lead selection stage. The primary objective of this group is the initial scale-up of promising leads for extensive physicochemical and biological testing. The challenge of the interface group involves overcoming synthetic issues within the rigid, accelerated timelines.
Assuntos
Tomada de Decisões Gerenciais , Desenho de Fármacos , Indústria Farmacêutica/organização & administração , Pesquisa Biomédica/economia , Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/tendências , Indústria Farmacêutica/economia , Indústria Farmacêutica/tendências , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/economia , Fatores de TempoRESUMO
The knowledge of SAR in a series of biphenyl anionic RSV inhibitors has been broadened by synthesis and testing of analogs with pyrimidine linkers. Generally, pyrimidine compounds were much harder to synthesize, and their anti-RSV activity was lower in comparison with triazine analogs.
Assuntos
Antivirais/farmacologia , Pirimidinas/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/síntese química , Pirimidinas/química , Vírus Sinciciais Respiratórios/metabolismo , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologiaRESUMO
Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.
Assuntos
2-Naftilamina/síntese química , Citomegalovirus/química , Naftalenos/síntese química , Inibidores de Proteases/síntese química , Serina Endopeptidases/química , Sulfonamidas/síntese química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Bases de Dados Factuais , Naftalenos/química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.