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1.
Bioorg Med Chem Lett ; 30(3): 126784, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31761656

RESUMO

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.

2.
Nat Commun ; 10(1): 47, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604750

RESUMO

Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved ß20-ß21 hairpin to improve potency.


Assuntos
Engenharia Química/métodos , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , HIV-1/fisiologia , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Nanopartículas/química , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Triazóis/química , Triazóis/farmacologia
3.
Bioorg Med Chem Lett ; 29(3): 466-470, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579797

RESUMO

Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.


Assuntos
Antraquinonas/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Imunoconjugados/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Antraquinonas/química , Anticorpos Monoclonais/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoconjugados/química , Neoplasias Pulmonares/patologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Angew Chem Int Ed Engl ; 57(44): 14560-14565, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30212610

RESUMO

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.


Assuntos
Aminoácidos/síntese química , Radicais Livres/química , Estereoisomerismo
5.
J Med Chem ; 61(14): 6308-6327, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29920093

RESUMO

The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.


Assuntos
Descoberta de Drogas , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Organofosfatos/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacologia , Pró-Fármacos/metabolismo , Triazóis/farmacologia , Ligação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Células CACO-2 , Membrana Celular/metabolismo , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Organofosfatos/farmacologia , Permeabilidade , Pró-Fármacos/farmacologia , Conformação Proteica , Ratos , Triazóis/metabolismo
6.
J Med Chem ; 61(1): 62-80, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29271653

RESUMO

Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials.


Assuntos
Descoberta de Drogas , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Organofosfatos/metabolismo , Organofosfatos/farmacologia , Piperazinas/metabolismo , Piperazinas/farmacologia , Pró-Fármacos/metabolismo , Ligação Viral/efeitos dos fármacos , Administração Oral , Ensaios Clínicos Fase I como Assunto , Humanos , Modelos Moleculares , Conformação Molecular , Organofosfatos/administração & dosagem , Organofosfatos/química , Piperazinas/administração & dosagem , Piperazinas/química
7.
Nat Chem Biol ; 13(10): 1115-1122, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28825711

RESUMO

The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the ß20-21 hairpin. In both structures, the ß20-21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.


Assuntos
Proteína gp120 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/química , Piperazinas/química , Bibliotecas de Moléculas Pequenas/química , Triazóis/química , Internalização do Vírus/efeitos dos fármacos , Cristalografia por Raios X , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Modelos Moleculares , Piperazinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
8.
Mol Pharmacol ; 92(3): 310-317, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28645932

RESUMO

The NaV1.7 voltage-gated sodium channel is implicated in human pain perception by genetics. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations results in congenital insensitivity to pain. Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a surrogate target strategy approach employing chimeras with the bacterial channel NaVAb. In this report we describe the design, synthesis, purification, and characterization of a chimera containing part of the voltage sensor domain 2 (VSD2) of NaV1.7. Importantly, this chimera, DII S1-S4, forms functional sodium channels and is potently inhibited by the NaV1.7 VSD2 targeted peptide toxin ProTx-II. Further, we show by [125I]ProTx-II binding and surface plasmon resonance that the purified DII S1-S4 protein retains high affinity ProTx-II binding in detergent. We employed the purified DII S1-S4 protein to create a scintillation proximity assay suitable for high-throughput screening. The creation of a NaV1.7-NaVAb chimera with the VSD2 toxin binding site provides an important tool for the identification of novel NaV1.7 inhibitors and for structural studies to understand the toxin-channel interaction.


Assuntos
Proteínas de Bactérias/química , Canal de Sódio Disparado por Voltagem NAV1.7/fisiologia , Proteínas Recombinantes de Fusão/química , Venenos de Aranha/metabolismo , Canais de Sódio Disparados por Voltagem/química , Proteínas de Bactérias/fisiologia , Sítios de Ligação , Células HEK293 , Humanos , Ressonância de Plasmônio de Superfície , Canais de Sódio Disparados por Voltagem/fisiologia
9.
J Med Chem ; 59(3): 1041-51, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26751161

RESUMO

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.


Assuntos
Encéfalo/metabolismo , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Niacinamida/administração & dosagem , Niacinamida/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade
10.
Nature ; 527(7577): 245-8, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26536115

RESUMO

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.


Assuntos
Antivirais/farmacologia , Compostos de Bifenilo/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Imidazóis/farmacologia , Proteínas não Estruturais Virais/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Linhagem Celular , Sinergismo Farmacológico , Quimioterapia Combinada , Hepacivirus/metabolismo , Hepatite C/virologia , Hepatócitos/transplante , Humanos , Camundongos , Modelos Moleculares , Conformação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína/efeitos dos fármacos , Reprodutibilidade dos Testes , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
11.
Bioorg Med Chem Lett ; 25(9): 1856-63, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25845281

RESUMO

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3ß. We identified several series of promising new GSK-3ß inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3ß inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.


Assuntos
Aminopiridinas/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Pirróis/química , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
12.
Proteins ; 83(2): 331-50, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25401969

RESUMO

HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure-activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel ß20-ß21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the "open state" four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development.


Assuntos
Proteína gp120 do Envelope de HIV/química , Inibidores da Fusão de HIV/química , Piperazinas/química , Triazóis/química , Sítios de Ligação , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Ligação Proteica , Homologia Estrutural de Proteína , Relação Estrutura-Atividade
13.
J Med Chem ; 57(5): 1643-72, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24621191

RESUMO

Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.


Assuntos
Descoberta de Drogas , Hepacivirus/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Hepacivirus/fisiologia , Proteínas não Estruturais Virais/metabolismo
14.
Protein Sci ; 23(6): 723-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24639329

RESUMO

New direct acting antivirals (DAAs) such as daclatasvir (DCV; BMS-790052), which target NS5A function with picomolar potency, are showing promise in clinical trials. The exact nature of how these compounds have an inhibitory effect on HCV is unknown; however, major resistance mutations appear in the N-terminal region of NS5A that include the amphipathic helix and domain 1. The dimeric symmetry of these compounds suggests that they act on a dimer of NS5A, which is also consistent with the presence of dimers in crystals of NS5A domain 1 from genotype 1b. Genotype 1a HCV is less potently affected by these compounds and resistance mutations have a greater effect than in the 1b genotypes. We have obtained crystals of domain 1 of the important 1a NS5A homologue and intriguingly, our X-ray crystal structure reveals two new dimeric forms of this domain. Furthermore, the high solvent content (75%) makes it ideal for ligand-soaking. Daclatasvir (DCV) shows twofold symmetry suggesting NS5A dimers may be of physiological importance and serve as potential binding sites for DCV. These dimers also allow for new conformations of a NS5A expansive network which could explain its operation on the membranous web. Additionally, sulfates bound in the crystal structure may provide evidence for the previously proposed RNA binding groove, or explain regulation of NS5A domain 2 and 3 function and phosphorylation, by domain 1.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Antivirais/farmacologia , Cristalografia por Raios X , Farmacorresistência Viral , Genótipo , Imidazóis/farmacologia
15.
Bioorg Med Chem ; 22(5): 1782-90, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24495863

RESUMO

Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Iminas/farmacocinética , Receptores de Serotonina/uso terapêutico , Animais , Humanos , Iminas/farmacologia , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade
16.
J Med Chem ; 57(5): 2013-32, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24521299

RESUMO

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Imidazóis/química , Imidazóis/farmacocinética , Espectroscopia de Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
17.
J Antimicrob Chemother ; 69(3): 573-81, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24128669

RESUMO

OBJECTIVES: In an 8 day monotherapy study of subjects infected with HIV-1 (subtype B) (NCT01009814), BMS-626529 (an attachment inhibitor that binds to HIV-1 envelope glycoprotein gp120), administered as the prodrug BMS-663068, produced substantial declines in plasma HIV-1 RNA. However, large variability in susceptibility to BMS-626529 was noted and virus with low susceptibility was less likely to be suppressed by BMS-663068 administration. The current analysis sought to investigate the genotypic correlates of susceptibility to BMS-626529. METHODS: In vitro selection experiments, evaluation of clinical samples of subtype B from the monotherapy study and evaluation of intrinsically resistant subtype AE viruses were conducted. Reverse genetics was used to identify key substitutions in envelope clones responsible for reduced susceptibility. RESULTS: An M426L or S375M change were the major substitutions associated with reductions in susceptibility to BMS-626529 in baseline samples of subtype B viruses from the monotherapy study, with M434I and M475I contributing to a lesser extent. Class resistance in subtype AE viruses was mapped to 375H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors. CONCLUSIONS: These data define key genotypic substitutions in HIV-1 gp120 that could confer phenotypic resistance to BMS-626529.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/genética , HIV-1/efeitos dos fármacos , Organofosfatos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Triazóis/farmacologia , Substituição de Aminoácidos , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Humanos , Dados de Sequência Molecular , Organofosfatos/uso terapêutico , Piperazinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Genética Reversa , Análise de Sequência de DNA , Triazóis/uso terapêutico
18.
Virology ; 444(1-2): 343-54, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23896639

RESUMO

The hepatitis C virus NS5A protein is an established and clinically validated target for antiviral intervention by small molecules. Characterizations are presented of compounds identified as potent inhibitors of HCV replication to provide insight into structural elements that interact with the NS5A protein. UV-activated cross linking and affinity isolation was performed with one series to probe the physical interaction between the inhibitors and the NS5A protein expressed in HCV replicon cells. Resistance mapping with the second series was used to determine the functional impact of specific inhibitor subdomains on the interaction with NS5A. The data provide evidence for a direct high-affinity interaction between these inhibitors and the NS5A protein, with the interaction dependent on inhibitor stereochemistry. The functional data supports a model of inhibition that implicates inhibitor binding by covalently combining distinct pharmacophores across an NS5A dimer interface to achieve maximal inhibition of HCV replication.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Farmacorresistência Viral , Humanos , Ligação Proteica
19.
J Med Chem ; 56(4): 1656-69, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23360431

RESUMO

A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c-l), and N-linked heterocycles (12m-u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.


Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Indóis/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Pirróis/síntese química , Triazinas/síntese química , Triazóis/síntese química , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Cristalografia por Raios X , HIV-1/fisiologia , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Teoria Quântica , Ratos , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologia , Ligação Viral/efeitos dos fármacos
20.
J Chem Phys ; 135(23): 231101, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22191857

RESUMO

We present a simple and practical method to include ligand electronic polarization in molecular dynamics (MD) simulation of biomolecular systems. The method involves periodically spawning quantum mechanical (QM) electrostatic potential (ESP) calculations on an extra set of computer processors using molecular coordinate snapshots from a running parallel MD simulation. The QM ESPs are evaluated for the small-molecule ligand in the presence of the electric field induced by the protein, solvent, and ion charges within the MD snapshot. Partial charges on ligand atom centers are fit through the multi-conformer restrained electrostatic potential (RESP) fit method on several successive ESPs. The RESP method was selected since it produces charges consistent with the AMBER/GAFF force-field used in the simulations. The updated charges are introduced back into the running simulation when the next snapshot is saved. The result is a simulation whose ligand partial charges continuously respond in real-time to the short-term mean electrostatic field of the evolving environment without incurring additional wall-clock time. We show that (1) by incorporating the cost of polarization back into the potential energy of the MD simulation, the algorithm conserves energy when run in the microcanonical ensemble and (2) the mean solvation free energies for 15 neutral amino acid side chains calculated with the quantum polarized fluctuating charge method and thermodynamic integration agree better with experiment relative to the Amber fixed charge force-field.


Assuntos
Ligantes , Modelos Químicos , Simulação de Dinâmica Molecular , Teoria Quântica , Algoritmos , Aminoácidos/química , Entropia , Íons/química , Ligação Proteica , Proteínas/química , Solventes/química , Eletricidade Estática
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