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1.
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
2.
ACS Med Chem Lett ; 9(5): 472-477, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795762

RESUMO

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

3.
Bioorg Med Chem ; 25(2): 496-513, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27914948

RESUMO

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.


Assuntos
Éteres/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Triazóis/farmacologia , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éteres/administração & dosagem , Éteres/química , Haplorrinos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/metabolismo , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
4.
J Med Chem ; 57(5): 1976-94, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23573957

RESUMO

A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.


Assuntos
Antivirais/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacologia , RNA Replicase/antagonistas & inibidores , Replicon/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Hepacivirus/fisiologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Inibidores de Proteases/química , Espectrometria de Massas por Ionização por Electrospray
5.
J Biomol Screen ; 19(4): 595-605, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24241710

RESUMO

Recent genetic evidence suggests that the diacylglycerol lipase (DAGL-α) isoform is the major biosynthetic enzyme for the most abundant endocannabinoid, 2-arachidonoyl-glycerol (2-AG), in the central nervous system. Revelation of its essential role in regulating retrograde synaptic plasticity and adult neurogenesis has made it an attractive therapeutic target. Therefore, it has become apparent that selective inhibition of DAGL-α enzyme activity with a small molecule could be a strategy for the development of novel therapies for the treatment of disease indications such as depression, anxiety, pain, and cognition. In this report, the authors present the identification of small-molecule inhibitor chemotypes of DAGL-α, which were selective (≥10-fold) against two other lipases, pancreatic lipase and monoacylglycerol lipase, via high-throughput screening of a diverse compound collection. Seven chemotypes of interest from a list of 185 structural clusters, which included 132 singletons, were initially selected for evaluation and characterization. Selection was based on potency, selectivity, and chemical tractability. One of the chemotypes, the glycine sulfonamide series, was prioritized as an initial lead for further medicinal chemistry optimization.


Assuntos
Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Linhagem Celular , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Cinética , Lipase Lipoproteica/metabolismo , Reprodutibilidade dos Testes , Especificidade por Substrato
6.
Proc Natl Acad Sci U S A ; 108(37): 15366-71, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21896751

RESUMO

Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.


Assuntos
Antivirais/farmacologia , Nucleoproteínas/química , Nucleoproteínas/metabolismo , Orthomyxoviridae/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Cristalografia por Raios X , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Hidrodinâmica , Camundongos , Modelos Moleculares , Nucleoproteínas/ultraestrutura , Orthomyxoviridae/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Bibliotecas de Moléculas Pequenas/uso terapêutico , Soluções
7.
Biochem Biophys Res Commun ; 411(4): 809-14, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21787747

RESUMO

Diacylglycerol lipase α is the key enzyme in the formation of the most prevalent endocannabinoid, 2-arachidonoylglycerol in the brain. In this study we identified the catalytic triad of diacylglycerol lipase α, consisting of serine 472, aspartate 524 and histidine 650. A truncated version of diacylglycerol lipase α, spanning residues 1-687 retains complete catalytic activity suggesting that the C-terminal domain is not required for catalysis. We also report the discovery and the characterization of fluorogenic and chromogenic substrates for diacylglycerol lipase α. Assays performed with these substrates demonstrate equipotent inhibition of diacylglycerol lipase α by tetrahydrolipastatin and RHC-20867 as compared to reactions performed with the native diacylglycerol substrate. Thus, confirming the utility of assays using these substrates for identification and kinetic characterization of inhibitors from pharmaceutical collections.


Assuntos
Lipase Lipoproteica/química , Catálise , Membrana Celular/enzimologia , Compostos Cromogênicos/química , Cicloexanonas/química , Fluorescência , Células HEK293 , Humanos , Lactonas/química , Lipase Lipoproteica/genética , Mutação , Orlistate , Especificidade por Substrato
8.
Bioorg Med Chem Lett ; 19(17): 5136-9, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19632112

RESUMO

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.


Assuntos
Fármacos Anti-HIV/química , Benzamidas/química , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Indóis/química , Piperazinas/química , Ligação Viral/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Linhagem Celular , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacologia , Humanos , Indóis/síntese química , Indóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Relação Estrutura-Atividade
9.
J Chem Inf Model ; 49(7): 1797-809, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19552372

RESUMO

An automated E-Novo protocol designed as a structure-based lead optimization tool was prepared through Pipeline Pilot with existing CHARMm components in Discovery Studio. A scaffold core having 3D binding coordinates of interest is generated from a ligand-bound protein structural model. Ligands of interest are generated from the scaffold using an R-group fragmentation/enumeration tool within E-Novo, with their cores aligned. The ligand side chains are conformationally sampled and are subjected to core-constrained protein docking, using a modified CHARMm-based CDOCKER method to generate top poses along with CDOCKER energies. In the final stage of E-Novo, a physics-based binding energy scoring function ranks the top ligand CDOCKER poses using a more accurate Molecular Mechanics-Generalized Born with Surface Area method. Correlation of the calculated ligand binding energies with experimental binding affinities were used to validate protocol performance. Inhibitors of Src tyrosine kinase, CDK2 kinase, beta-secretase, factor Xa, HIV protease, and thrombin were used to test the protocol using published ligand crystal structure data within reasonably defined binding sites. In-house Respiratory Syncytial Virus inhibitor data were used as a more challenging test set using a hand-built binding model. Least squares fits for all data sets suggested reasonable validation of the protocol within the context of observed ligand binding poses. The E-Novo protocol provides a convenient all-in-one structure-based design process for rapid assessment and scoring of lead optimization libraries.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/química , Quinase 2 Dependente de Ciclina/metabolismo , Fator Xa/química , Fator Xa/metabolismo , Inibidores do Fator Xa , Protease de HIV/química , Protease de HIV/metabolismo , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Proteínas/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/química , Trombina/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/química , Quinases da Família src/metabolismo
10.
Bioorg Med Chem Lett ; 19(7): 1977-81, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19251416

RESUMO

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.


Assuntos
Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Ligação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/prevenção & controle , Humanos , Indóis/química , Indóis/farmacocinética , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 17(17): 4784-90, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17616396

RESUMO

The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors 4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems.


Assuntos
Antivirais/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/metabolismo , Proteínas Virais de Fusão/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Elétrons , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular
12.
J Chem Inf Model ; 46(3): 1060-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16711725

RESUMO

A process for objective identification and filtering of undesirable compounds that contribute to high-throughput screening (HTS) deck promiscuity is described. Two methods of mapping hit promiscuity have been developed linking SMARTS-based structural queries with historical primary HTS data. The first compares an expected assay hit rate to actual hit rates. The second examines the propensity of an individual compound to hit multiple assays. Statistical evaluation of the data indicates a correlation between the resultant functional group filters and compound promiscuity. These data corroborate a number of commonly applied filters as well as producing some unexpected results. Application of these models to HTS collection triage reduced the number of in-house compounds considered for screening by 12%. The implications of these findings are further discussed in the context of the HTS screening set and combinatorial library design as well as compound acquisition.


Assuntos
Desenho de Fármacos , Indústria Farmacêutica , Pesquisa Empírica
13.
Bioorg Med Chem Lett ; 16(5): 1115-22, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16368233

RESUMO

The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Fusão de Membrana/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/fisiologia , Água/química , Aminas/química , Animais , Antivirais/efeitos adversos , Antivirais/síntese química , Benzimidazóis/efeitos adversos , Benzimidazóis/síntese química , Camundongos , Estrutura Molecular , Ratos , Sigmodontinae , Solubilidade , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 14(5): 1133-7, 2004 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-14980651

RESUMO

Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/fisiologia
15.
J Org Chem ; 61(2): 451-454, 1996 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-11666959

RESUMO

Four of the previously reported compounds obtained from the acid-catalyzed condensation of indole with acetone are now assigned the following structures: cis-4,4a,9,9a-tetrahydro-2-(1H-indol-3-yl)-4,4-dimethyl-3H-carbazole (2a), 1,1',4,4'-tetrahydro-1,1,1',1'-tetramethyl-3,3'(2H,2'H)-spirobi[cyclopent[b]indole] (4), 4,4a-dihydro-2-(3-1H-indolyl)-4,4-dimethyl-3H-carbazol-4a-ol (7), and 5-(2-aminophenyl)-1,3,4,5-tetrahydro-1,1,4,4-tetramethylcyclopent[kl]acridine (8). The structure of the novel rearrangement product 8 was solved by an X-ray crystal structure determination. The two previously reported autoxidation products of 4 are now assigned the following structures: 1,3',4,4'-tetrahydro-1,1,4',4'-tetramethyl-cis-dispiro[cyclopent[b]indole-3(2H),2'(5'H)-furan-5',3"-[3H]-indol]-2"(1"H)-one (5) and 1,4-dihydro-1,1,5',5'-tetramethylspiro[cyclopent[b]indole-3(2H),3'(4'H)-1-benzazocine]-2'(1'H),6'(5'H)-dione (6).

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