RESUMO
Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.
Assuntos
Antivirais , Piridinas , Animais , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Camundongos , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Relação Estrutura-Atividade , Ovinos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacosRESUMO
In the context of growing impetus to develop new molecular scaffolds as well as a variety of 3D fragments to escape from flatland, we have reintroduced the accessibility of the underexplored azaheterocyclic amidrazones as promising bioisosteres. Herein, we present an original and versatile approach to synthesize cyclic amidrazones functionalized at different positions of the scaffold in view of diversifying the substitution pattern towards multifunctionalization, extension or fusion of the ring system and 3D-shaping of fragments. This unprecedented synthetic route represents a sweet achievement to cover further lead-like chemical space.
RESUMO
A linear sequence to access a novel series of C-nucleosides bearing a quaternary carbon at the anomeric position tethered to a 4-substituted 1,2,3-triazole ring is described. Most of the compounds were obtained from a C-1 alkynyl furanoside, by a tandem or two-step CuAAC/functionalisation sequence, along with a diastereoselective cyanation of the furanoside derivatives in acidic conditions.
Assuntos
Antivirais , Nucleosídeos , Antivirais/farmacologia , TriazóisRESUMO
In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Desenho de Fármacos , Indóis/síntese química , Indóis/farmacologia , Proteínas Virais/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Cães , Humanos , Indóis/química , Indóis/farmacocinética , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Mycobacterium tuberculosis infection results in more than two million deaths per year and is the leading cause of mortality in people infected with HIV. A new structural class of antimycobacterials, the diarylquinolines, has been synthesized and is being highly effective against both M. tuberculosis and multidrug-resistant tuberculosis. As diarylquinolines are biologically active only under their ( R,S) stereoisomeric form, it is essential to differentiate the stereoisomers ( R,S) and ( R,R). To achieve this, tandem mass spectrometry and ion mobility spectrometry-mass spectrometry have been performed with 10 diarylquinoline diastereomers couples. In this study, we investigated cationization with alkali metal cations and several ion mobility drift gases in order to obtain diastereomer differentiations. We have shown that diastereomers of the diarylquinolines family can be differentiated separately by tandem mass spectrometry and in mixture by ion mobility spectrometry-mass spectrometry. However, although the structure of each diastereomer is close, several behaviors could be observed concerning the cationization and the ion mobility spectrometry separation. The ion mobility spectrometry isomer separation efficiency is not easily predictable; it was however observed for all diastereomeric couples with a significant improvement of separation using alkali adducts compared to protonated molecules. With the use of drift gas with higher polarizability only an improvement of separation was obtained in a few cases. Finally, a good correlation of the experimental collision cross section (relative to three-dimensional structure of ions) and the theoretical collision cross section has been shown.
Assuntos
Antituberculosos/química , Diarilquinolinas/química , Espectrometria de Mobilidade Iônica/métodos , Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Humanos , Estrutura Molecular , Estereoisomerismo , Tuberculose/tratamento farmacológicoRESUMO
Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.
Assuntos
Antituberculosos/síntese química , Diarilquinolinas/química , Compostos Heterocíclicos/química , Administração Oral , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Diarilquinolinas/farmacocinética , Diarilquinolinas/farmacologia , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
RESUMO
Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.
RESUMO
Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.
Assuntos
Complexos de ATP Sintetase/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Complexos de ATP Sintetase/genética , Trifosfato de Adenosina/biossíntese , Sequência de Aminoácidos , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Farmacorresistência Bacteriana/genética , Bactérias Gram-Positivas/crescimento & desenvolvimento , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Quinolinas/química , Quinolinas/toxicidade , Alinhamento de Sequência , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S(RN)1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 µM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC(50) > 100 µM).
Assuntos
Fármacos Anti-HIV/síntese química , Benzoxazóis/síntese química , Transcriptase Reversa do HIV/metabolismo , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfetos/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Mutação , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologiaRESUMO
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis and resistance to current anti-TB drugs call for the discovery and development of new effective anti-TB drugs. TMC207 is the lead candidate of a novel class of antimycobacterial agents, the diarylquinolines, which specifically inhibit mycobacterial ATP synthase and displays high activity against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis. This article covers both synthesis pathways as well as qualitative and quantitative analyses of the structure-activity relationships of the diarylquinoline series on Mycobacterium smegmatis activity.
Assuntos
Antituberculosos/síntese química , Descoberta de Drogas/métodos , Quinolinas/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Diarilquinolinas , Farmacorresistência Bacteriana Múltipla , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Quantitativa Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/toxicidadeRESUMO
Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments.
Assuntos
Trifosfato de Adenosina/metabolismo , ATPases Bacterianas Próton-Translocadoras/metabolismo , Mycobacterium smegmatis/enzimologia , Quinolinas/metabolismo , Trifosfato de Adenosina/química , Antituberculosos/química , Antituberculosos/metabolismo , ATPases Bacterianas Próton-Translocadoras/química , ATPases Bacterianas Próton-Translocadoras/genética , Sítios de Ligação/genética , Ligação Competitiva/efeitos dos fármacos , Diarilquinolinas , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Ionóforos/farmacologia , Cinética , Modelos Moleculares , Estrutura Molecular , Mutação , Nitrilas/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Força Próton-Motriz , Prótons , Quinolinas/química , Eletricidade Estática , Ressonância de Plasmônio de SuperfícieRESUMO
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Assuntos
Antituberculosos/uso terapêutico , Descoberta de Drogas , Tuberculose/tratamento farmacológico , Antituberculosos/química , Antituberculosos/farmacologia , Respiração Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Farmacorresistência Bacteriana , Resistência a Múltiplos Medicamentos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Recently, Brinster et al. suggested that type II fatty-acid biosynthesis (FASII) is not a suitable antibacterial target for Gram-positive pathogens because they use fatty acids directly from host serum rather than de novo synthesis. Their findings, if confirmed, are relevant for further scientific and financial investments in the development of new drugs targeting FASII. We present here in vitro and in vivo data demonstrating that their observations do not hold for Staphylococcus aureus, a major Gram-positive pathogen causing several human infections. The observed differences among Gram-positive pathogens in FASII reflects heterogeneity either in fatty-acid synthesis or in the capacity for fatty-acid uptake from the environment.
Assuntos
Ácidos Graxos/biossíntese , Staphylococcus aureus/metabolismo , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Camundongos , Reprodutibilidade dos Testes , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Triclosan/farmacologiaRESUMO
A series of C-5 methyl substituted 4-arylthio- and 4-aryloxy-3-iodopyridin-2(1H)-ones has been synthesized as new pyridinone analogues for their evaluation as anti-HIV inhibitors. The optimization at the 5-position was developed through an efficient use of the key intermediates 5-ethoxycarbonyl- and 5-cyano-pyridin-2(1H)-ones (14 and 15). Biological studies revealed that several compounds show potent HIV-1 reverse transcriptase inhibitory properties, for example, compounds 93 and 99 are active at 0.6-50 nM against wild type HIV-1 and a panel of major simple/double HIV mutant strains.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV/efeitos dos fármacos , Iodopiridonas/síntese química , Iodopiridonas/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular , HIV/enzimologia , HIV/genética , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , Humanos , Concentração Inibidora 50 , Iodopiridonas/química , Mutação , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 microM) and had modest activity (MICs, 8 to 16 microg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 microg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with >or=2x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (Assuntos
Antibacterianos/farmacologia
, Bactérias/efeitos dos fármacos
, Inibidores Enzimáticos/farmacologia
, Peptídeo Sintases/antagonistas & inibidores
, Quinolinas/farmacologia
, Antibacterianos/química
, Enterococcus faecalis/efeitos dos fármacos
, Enterococcus faecium/efeitos dos fármacos
, Inibidores Enzimáticos/química
, Escherichia coli/efeitos dos fármacos
, Testes de Sensibilidade Microbiana
, Estrutura Molecular
, Peptídeo Sintases/genética
, Peptídeo Sintases/fisiologia
, Quinolinas/química
, Staphylococcus aureus/efeitos dos fármacos
RESUMO
A diastereodivergent addition of allenylzincs to aryl glyoxylates was observed depending on the method used for the preparation of the allenylzinc reagent. The allenylzincs were prepared from propargylic benzoates in the presence of a palladium catalyst or by metalation of alkynes.
Assuntos
Alcinos/síntese química , Benzoatos/química , Glioxilatos/química , Compostos Organometálicos/síntese química , Alcinos/química , Brometos/química , Catálise , Estrutura Molecular , Compostos Organometálicos/química , Paládio/química , Estereoisomerismo , Compostos de Zinco/químicaRESUMO
The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC(50)] of >200 microM) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC(50) of 10 nM). Also, oxygen consumption in mouse liver and bovine heart mitochondria showed very low sensitivity for TMC207. These results suggest that TMC207 may not elicit ATP synthesis-related toxicity in mammalian cells. ATP synthase, although highly conserved between prokaryotes and eukaryotes, may still qualify as an attractive antibiotic target.
Assuntos
Antituberculosos/farmacologia , Células Eucarióticas/enzimologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Bovinos , Linhagem Celular , Linhagem Celular Tumoral , Diarilquinolinas , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Camundongos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/metabolismo , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/isolamento & purificação , Consumo de Oxigênio/efeitos dos fármacos , Sensibilidade e EspecificidadeRESUMO
An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment.
Assuntos
Trifosfato de Adenosina/química , Regulação Bacteriana da Expressão Gênica , Homeostase , Mycobacterium/metabolismo , Quinolinas/farmacologia , Antituberculosos/farmacologia , ATPases Mitocondriais Próton-Translocadoras/química , Modelos Biológicos , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/metabolismo , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Óxido Nítrico/química , Oxigênio/química , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.