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1.
Bioorg Med Chem Lett ; 26(15): 3429-35, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27377328

RESUMO

We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.


Assuntos
Antivirais/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Quinoxalinas/farmacologia , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Proteínas da Matriz Viral/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Ebolavirus/química , Células HEK293 , Humanos , Marburgvirus/química , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 26(5): 1480-1484, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26852364

RESUMO

The HIV-1 Nef accessory factor enhances viral replication and promotes immune system evasion of HIV-infected cells, making it an attractive target for drug discovery. Recently we described a novel class of diphenylpyrazolodiazene compounds that bind directly to Nef in vitro and inhibit Nef-dependent HIV-1 infectivity and replication in cell culture. However, these first-generation Nef antagonists have several structural liabilities, including an azo linkage that led to poor oral bioavailability. The azo group was therefore replaced with either a one- or two-carbon linker. The resulting set of non-azo analogs retained nanomolar binding affinity for Nef by surface plasmon resonance, while inhibiting HIV-1 replication with micromolar potency in cell-based assays without cytotoxicity. Computational docking studies show that these non-azo analogs occupy the same predicted binding site within the HIV-1 Nef dimer interface as the original azo compound. Computational methods also identified a hot spot for inhibitor binding within this site that is defined by conserved HIV-1 Nef residues Asp108, Leu112, and Pro122. Pharmacokinetic evaluation of the non-azo B9 analogs in mice showed that replacement of the azo linkage dramatically enhanced oral bioavailability without substantially affecting plasma half-life or clearance. The improved oral bioavailability of non-azo diphenylpyrazolo Nef antagonists provides a starting point for further drug lead optimization in support of future efficacy testing in animal models of HIV/AIDS.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Administração Oral , Animais , Fármacos Anti-HIV/administração & dosagem , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , HIV-1/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Replicação Viral/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 25(2): 378-83, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25496770

RESUMO

The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxidative phosphorylation (OxPhos) was identified as a novel target for drug discovery research. Consequently, a library of ∼10,000 compounds was screened using a membrane-based ATP synthesis assay. One hit identified was the 2-iminobenzimidazole 1 that inhibited the OxPhos of A. baumannii with a modestly high selectivity against mitochondrial OxPhos, and displayed an MIC of 25µM (17µg/mL) against the pathogen. The 2-iminobenzimidazole 1 was found to inhibit the type 1 NADH-quinone oxidoreductase (NDH-1) of A. baumannii OxPhos by a biochemical approach. Among various derivatives that were synthesized to date, des-hydroxy analog 5 is among the most active with a relatively tight SAR requirement for the N'-aminoalkyl side chain. Analog 5 also showed less cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the potential for this series of compounds as anti-Acinetobacter agents. Additional SAR development and target validation is underway.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Infecções por Acinetobacter/microbiologia , Animais , Antibacterianos/química , Antineoplásicos/química , Benzimidazóis/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células NIH 3T3 , Quinona Redutases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
ACS Med Chem Lett ; 15(1): 123-131, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38229758

RESUMO

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1, we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution. Our strategy involved the use of predicted volume ligand efficiency to advance compounds with greater potential for low human doses down our screening funnel. We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to rationalize P-gp SAR. Together, our strategies enabled the alignment of a lower human dose with reduced P-gp efflux, and favorable PXR selectivity for the discovery of compound 12.

5.
ACS Med Chem Lett ; 14(2): 146-155, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36793422

RESUMO

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.

6.
J Virol ; 84(15): 7625-33, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20484498

RESUMO

HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.


Assuntos
Inibidores Enzimáticos/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , Naftiridinas/metabolismo , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Ribonuclease H do Vírus da Imunodeficiência Humana/química , Sítios de Ligação , Domínio Catalítico , Cátions/metabolismo , Cristalografia por Raios X , HIV , Transcriptase Reversa do HIV/metabolismo , HIV-1/química , Humanos , Metais/metabolismo , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo
7.
Bioorg Med Chem Lett ; 20(22): 6754-7, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20869872

RESUMO

Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 µM, HIV RT RNase H; 13 µM, HIV RT-polymerase; 24 µM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 µM) with a modest window with respect to cytotoxicity (CC(50)=3.3 µM).


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/farmacologia , HIV-1/enzimologia , Ribonuclease H/antagonistas & inibidores , Fármacos Anti-HIV/química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Naftiridinas/química , Naftiridinas/farmacologia
8.
ACS Med Chem Lett ; 8(12): 1292-1297, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259750

RESUMO

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

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