RESUMO
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg2+-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed in vitro cidality as well as intracellular activity against M. tuberculosis in macrophages. Evidence for the DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response seen in a recA reporter strain of M. tuberculosis. Pharmacokinetic properties of 22 supported evaluation of efficacy in an acute model of M. tuberculosis infection, where modest reduction in CFU numbers was seen. This work offers promise for deriving a novel drug class of tuberculosis agent without preexisting clinical resistance.
Assuntos
Mycobacterium tuberculosis , Tuberculose , DNA Girase/genética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Inibidores da Topoisomerase II/farmacologia , Tuberculose/tratamento farmacológicoRESUMO
The use of antibiotics directly correlates with the increase in antimicrobial resistance (AMR). Targeting novel antibiotics to patients with multidrug-resistant (MDR) pathogens should enhance their durability and slow development of resistance. The discovery, development, and clinical adoption of pathogen-targeted antibiotics have been hampered by technical and regulatory challenges. Growing insights into bacterial physiology and mechanisms of resistance, innovative clinical trial designs, streamlined regulatory approval pathways, and availability of rapid bacterial diagnostics are recent developments that can help address those challenges. Pathogen-targeted antibiotics provide an opportunity to treat patients with the right drug at the right time, leading to improved patient outcomes and better antimicrobial stewardship. Patient-centered pricing and reimbursement reform is needed to incentivize innovation.
Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Desenvolvimento de Medicamentos , Descoberta de Drogas , Animais , Gestão de Antimicrobianos , Bactérias/efeitos dos fármacos , Pesquisa Biomédica , Humanos , Transferência de TecnologiaRESUMO
Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Aciltransferases/antagonistas & inibidores , Aciltransferases/genética , Aciltransferases/metabolismo , Adenosina/metabolismo , Adenosina/farmacologia , Antibacterianos/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Ceftazidima/metabolismo , Ceftazidima/farmacologia , Parede Celular/química , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Cromatografia Líquida , DNA Bacteriano/antagonistas & inibidores , DNA Bacteriano/biossíntese , Escherichia coli/genética , Escherichia coli/metabolismo , Fosfomicina/análogos & derivados , Fosfomicina/metabolismo , Fosfomicina/farmacologia , Expressão Gênica , Células HEK293 , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Espectrometria de Massas , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Núcleosídeo-Fosfato Quinase/genética , Núcleosídeo-Fosfato Quinase/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Terpenos/antagonistas & inibidores , Terpenos/metabolismo , Treonina/análogos & derivados , Treonina/metabolismo , Treonina/farmacologia , Triclosan/metabolismo , Triclosan/farmacologiaRESUMO
With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Barbitúricos/farmacologia , Barbitúricos/uso terapêutico , Gonorreia/tratamento farmacológico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêutico , Adulto , Animais , Antibacterianos/química , Barbitúricos/química , DNA Topoisomerases Tipo II/química , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Feminino , Fluoroquinolonas/farmacologia , Gonorreia/microbiologia , Haplorrinos , Humanos , Isoxazóis , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Molecular , Morfolinas , Mutação , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Oxazolidinonas , Ratos , Compostos de Espiro/química , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Adulto JovemAssuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Farmacorresistência Bacteriana , Antibacterianos/química , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Medicina de Precisão , Bibliotecas de Moléculas Pequenas , Resistência beta-LactâmicaRESUMO
Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Fatores Imunológicos/administração & dosagem , Ensaios Clínicos como Assunto , HumanosRESUMO
BACKGROUND: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies. METHODS: Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information. Virological response (HIV-1 RNA<50 copies/ml at week 48) using each of these methods was compared with a commonly used method of counting active drugs. Baseline predictors of virological response, including weighted or unweighted scoring, maraviroc use, baseline CD4(+) T-cell count, HIV-1 plasma viral load and tropism, were assessed by logistic regression modelling. RESULTS: Genotypic or phenotypic weighted methods were similarly predictive of virological response and better than counting active drugs. Weighted scoring and baseline CD4(+) T-cell count were the strongest predictors of virological response (P<0.0001): ≈70% of maraviroc patients with a weighted score ≥2 had a virological response, rising to ≈80% when the baseline CD4(+) T-cell count was ≥50 cells/mm(3). CONCLUSIONS: Approximately 80% of patients with a CD4(+) T-cell count ≥50 cells/mm(3) receiving maraviroc with the equivalent of at least two fully active agents achieved HIV-1 RNA<50 copies/ml at week 48 in the MOTIVATE studies. Genotypic and phenotypic weighted scores were similarly predictive of virological response.
Assuntos
Fármacos Anti-HIV/farmacologia , Cicloexanos/administração & dosagem , Cicloexanos/uso terapêutico , Farmacorresistência Viral , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Antagonistas dos Receptores CCR5 , Contagem de Linfócito CD4 , Ensaios Clínicos Fase III como Assunto , Cicloexanos/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Genótipo , Inibidores da Fusão de HIV/administração & dosagem , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Modelos Logísticos , Maraviroc , Testes de Sensibilidade Microbiana , Fenótipo , Valor Preditivo dos Testes , RNA Viral/sangue , Linfócitos T/virologia , Resultado do Tratamento , Triazóis/farmacologia , Carga ViralRESUMO
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Assuntos
Fármacos Anti-HIV/síntese química , Compostos Azabicíclicos/síntese química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Imidazóis/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Linhagem Celular , Cricetinae , Cicloexanos/farmacologia , Cães , Farmacorresistência Viral , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , HIV-1/isolamento & purificação , Humanos , Imidazóis/química , Imidazóis/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Maraviroc , Modelos Moleculares , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia , TropanosRESUMO
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
Assuntos
Fármacos Anti-HIV/química , Proteínas do Capsídeo/antagonistas & inibidores , Substituição de Aminoácidos , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Proteínas do Capsídeo/genética , Linhagem Celular , Cristalografia por Raios X , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Proteínas do Vírus da Imunodeficiência Humana , Humanos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.
Assuntos
HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Farmacorresistência Viral/genética , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Nitrilas , PirazóisRESUMO
A low-molecular-weight human immunodeficiency virus type 1 (HIV-1) inhibitor, PF-68742 (molecular weight, 573), has been identified in a high-throughput screen for compounds that block HIV-1 envelope glycoprotein (Env)-mediated fusion. The compound is shown to be potent against R5 and X4 isolates in both cell-cell fusion and antiviral assays (50% effective concentrations of approximately 0.1 to 1 muM). Postfusion and HIV-1 pseudotyping control experiments confirm that PF-68742 is an entry inhibitor with Env as the specific target for antiviral action. PF-68742 was not able to block binding of monomeric gp120 to soluble CD4 or the binding of gp120:CD4 complexes to cell-associated CCR5, thus distinguishing PF-68742 from described gp120 antagonists and coreceptor binders. Escape variants of HIV-1(NL4-3) were selected, and all resistant viruses were found to contain a common G514R (HxB2 numbering) mutation in Env, located proximal to the furin cleavage site in the fusion peptide of gp41. When introduced into wild-type NL4-3 gp41, G514R conferred resistance to PF-68742. Resistance via G514R is shown to be associated with enhancement of virion infectivity by PF-68742 that may result from altered properties of inhibitor-bound Env, rather than from a loss of compound binding. Wild-type viruses and those with substitutions in the disulfide loop (DSL) region of gp41 were also examined for PF-68742 sensitivity. Here, complete resistance to PF-68742 was found to occur through changes outside of position 514, including in the gp41 DSL region. The results highlight PF-68742 as a starting point for novel therapies against HIV-1 and provide new insights into models of Env-mediated fusion.
Assuntos
Antagonistas dos Receptores CCR5 , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Piridonas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Sulfonamidas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/genética , Inibidores da Fusão de HIV/química , Humanos , Dados de Sequência Molecular , Estrutura Molecular , Peso Molecular , Mutação , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Alinhamento de SequênciaRESUMO
A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Vírion/efeitos dos fármacos , Vírion/metabolismo , Fármacos Anti-HIV/química , Western Blotting , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Células Cultivadas , Células HeLa , Humanos , Estrutura MolecularRESUMO
Our efforts to reduce overall lipophilicity and increase ligand-lipophilicity efficiency (LLE) by modification of the 3- and 5-substituents of pyrazole 1, a novel non-nucleoside HIV reverse transcriptase inhibitor (NNRTI) prototype were unsuccessful. In contrast replacement of the substituted benzyl group with corresponding phenylthio or phenoxy groups resulted in marked improvements in potency, ligand efficiency (LE) and LLE.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/química , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Fenômenos Químicos , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Nitrilas/química , Pirazóis/química , Inibidores da Transcriptase Reversa/química , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Nitrilas/síntese química , Nitrilas/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinéticaRESUMO
The design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on a pyrazole template is described. These compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/química , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.
Assuntos
Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Piperazinas/química , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Desenho de Fármacos , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
Assuntos
Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Isoquinolinas/química , Ácidos Nicotínicos/química , Animais , Células Cultivadas , Desenho de Fármacos , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The G protein-coupled chemokine (C-C motif) receptor, CCR5, was originally characterized as a protein responding functionally to a number of CC chemokines. As with chemokine receptors in general, studies indicate that CCR5 plays a role in inflammatory responses to infection, although its exact role in normal immune function is not completely defined. The vast majority of research into CCR5 has been focused on its role as an essential and predominant coreceptor for HIV-1 entry into host immune cells. Discovery of this role was prompted by the elucidation that individuals homozygous for a 32 bp deletion in the CCR5 gene do not express the receptor at the cell surface, and as a consequence, are remarkably resistant to HIV-1 infection, and apparently possess no other clear phenotype. Multiple studies followed with the ultimate aim of identifying drugs that functionally and physically blocked CCR5 to prevent HIV-1 entry, and thus provide a completely new approach to treating infection and AIDS, the world's biggest infectious disease killer. To this end, functional antagonists with potent anti-HIV-1 activity have been discovered, as best exemplified by maraviroc, the first new oral drug for the treatment of HIV-1 infection in 10 years. In this chapter, the specific methods used to characterize CCR5 primary pharmacology and apply the data generated to enable drug discovery, notably maraviroc, for the treatment of HIV infection and potentially inflammatory-based indications, are described.
Assuntos
Antagonistas dos Receptores CCR5 , Descoberta de Drogas/métodos , Receptores CCR5/metabolismo , Animais , Fármacos Anti-HIV/uso terapêutico , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Maraviroc , Receptores CCR5/genética , Triazóis/uso terapêuticoRESUMO
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.