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1.
ACS Med Chem Lett ; 2(2): 148-53, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900294

RESUMO

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.

2.
Bioorg Med Chem Lett ; 19(16): 4857-62, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19596574

RESUMO

A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure-activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series. Further optimization of the isatin oxime derivatives focused on introduction of nitrogen atoms to the isatin phenyl ring to provide a series of aza-isatin oximes with significantly improved PK properties. Several aza-isatin oximes analogs displayed targeted metabolic stability in HLM and permeability across a confluent monolayer of CaCo-2 cells. These studies identified several compounds, including 18i, 18j and 18n that demonstrated antiviral activity in the BALB/c mouse model of RSV infection following oral dosing.


Assuntos
Antivirais/química , Isatina/química , Oximas/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade
3.
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
4.
Bioorg Med Chem Lett ; 17(16): 4592-8, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17576060

RESUMO

Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Vírus Sinciciais Respiratórios/genética , Vírus Sinciciais Respiratórios/metabolismo , Relação Estrutura-Atividade , Replicação Viral
5.
Proc Natl Acad Sci U S A ; 101(42): 15046-51, 2004 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-15469910

RESUMO

Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a "trimer-of-hairpins" structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.


Assuntos
Fusão de Membrana/efeitos dos fármacos , Fusão de Membrana/fisiologia , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/fisiologia , Sequência de Aminoácidos , Antivirais/farmacologia , Benzimidazóis/farmacologia , Sítios de Ligação , Modelos Moleculares , Dados de Sequência Molecular , Marcadores de Fotoafinidade , Conformação Proteica , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/genética , Vírus Sinciciais Respiratórios/fisiologia , Proteínas Virais de Fusão/genética
6.
Antimicrob Agents Chemother ; 48(7): 2448-54, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15215093

RESUMO

BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was approximately 7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Animais , Antivirais/farmacocinética , Área Sob a Curva , Benzimidazóis/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Sigmodontinae , Proteínas Virais de Fusão/antagonistas & inibidores
7.
Antimicrob Agents Chemother ; 48(2): 413-22, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14742189

RESUMO

BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Mapeamento Cromossômico , Clonagem Molecular , DNA Complementar/genética , Farmacorresistência Viral , Genótipo , Células Gigantes/patologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/genética , Temperatura , Proteínas Virais de Fusão/biossíntese , Ensaio de Placa Viral , Proteínas Virais/biossíntese
8.
Bioorg Med Chem Lett ; 13(13): 2141-4, 2003 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-12798322

RESUMO

Structure-activity relationships surrounding the dialkylamino side chain of a series of benzotriazole-derived inhibitors of respiratory syncytial virus fusion based on the screening lead 1a were examined. The results indicate that the topology of the side chain is important but the terminus element offers considerable latitude to modulate physical properties.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia , Alquilação , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Desenho de Fármacos , Humanos , Indicadores e Reagentes , Cetonas/síntese química , Cetonas/química , Relação Estrutura-Atividade
9.
J Biol Chem ; 278(4): 2403-10, 2003 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-12441342

RESUMO

Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA , Relação Dose-Resposta a Droga , Fenofibrato/farmacologia , Humanos , Hidrocarbonetos Fluorados , Hipolipemiantes/farmacologia , Concentração Inibidora 50 , Ligantes , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Receptores X do Fígado , Camundongos , Modelos Químicos , Receptores Nucleares Órfãos , Ligação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Contagem de Cintilação , Sulfonamidas , Fatores de Tempo , Ativação Transcricional , Transfecção , Células Tumorais Cultivadas
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