RESUMO
A versatile one-pot procedure for the preparation of 2-alkyl-substituted N-arylindoles is described. The method combines a visible light-mediated Ni/Ir-photoredox dual catalytic N-arylation of alkynyl anilines under continuous flow conditions with a subsequent base-mediated cyclization to afford the desired substituted indoles. The initial Ni/Ir photoredox-promoted N-arylation of alkynylanilines proceeds efficiently in a continuous flow to afford the desired products in moderate to excellent yields with a short residence time (20 min) and mild conditions at ambient temperature and without the exclusion of air. The methodology was amenable for a multi-gram scale-up to deliver 2-alkyl-N-arylindoles in high yields followed with only a single purification step.
RESUMO
A photoredox protocol that uses a heteroleptic Cu (I) complex, [Cu(dq)(BINAP)]BF4, has been developed for the photodeprotection of benzenesulfonyl-protected N-heterocycles. A range of substrates was examined, including indazoles, indoles, pyrazoles, and benzimidazole, featuring both electron-rich and electron-deficient substituents, giving good yields of the N-heterocycle products with broad functional group tolerance. This transformation was also found to be amenable to flow reaction conditions.
RESUMO
The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3-Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3-Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction.
RESUMO
C-H functionalization of electron-deficient heteroarenes using commercial unactivated alkyl halides through reductive quenching photoredox catalysis was developed. Mainstream approaches rely on the use of an excess of strong acids that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving the functionalization of other carbons unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by relying on a combination of conjugate and halogen ortho-directing effects. Overall, this methodology gives quick access to a variety of alkylated heteroarenes that will be of interest to medicinal chemistry programs.
RESUMO
A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form Csp3-Csp2 bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines.
RESUMO
VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.
Assuntos
Antivirais/farmacologia , Compostos Aza/farmacologia , Indóis/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Compostos Aza/química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Vírus da Influenza A/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas , Pirimidinas , Pirróis , Relação Estrutura-Atividade , Proteínas Virais/metabolismoRESUMO
Chronic schistosomiasis affects either the genitourinary or gastrointestinal tract. Rarely, schistosomes cause ectopic disease, such as in the case of a South African woman from a non-endemic province, who presented with suspected pericardial tamponade because of tuberculosis. However, histology and polymerase chain reaction from pericardial biopsy confirmed Schistosoma haematobium. A finding of mediastinal non-Hodgkin lymphoma came to light when our patient's clinical condition unexpectedly deteriorated. Contribution: This case highlights an unusual manifestation of schistosomiasis.
RESUMO
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
Assuntos
Indóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Ratos , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-AtividadeRESUMO
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
Assuntos
Catepsina K/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Administração Oral , Amidas/química , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Catepsina K/metabolismo , Cães , Etilaminas/síntese química , Etilaminas/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , RatosRESUMO
In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Elongases de Ácidos Graxos/antagonistas & inibidores , Pirimidinas/farmacologia , Administração Oral , Adrenoleucodistrofia/tratamento farmacológico , Animais , Disponibilidade Biológica , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Éteres/química , Células HEK293 , Humanos , Macaca fascicularis , Camundongos , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , RatosRESUMO
Substoichiometric amounts of ZnCl(2) promote the room temperature, Pd/P(t-Bu)(3)-catalyzed cross-coupling of aryl bromides with alkynes. Pd(I) dimer 1 is demonstrated to be a particularly active precatalyst for this reaction. The reaction is general for a wide variety of aryl bromides.
Assuntos
Alcinos/química , Cloretos/química , Hidrocarbonetos Bromados/química , Temperatura , Compostos de Zinco/química , Estrutura Molecular , EstereoisomerismoRESUMO
Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.
Assuntos
Compostos de Bifenilo/síntese química , Catepsina K/antagonistas & inibidores , Catepsina K/química , Química Farmacêutica/métodos , Cetonas/química , Nitrilas/química , Animais , Bile/metabolismo , Compostos de Bifenilo/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cetonas/análise , Modelos Químicos , Osteoporose/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
RESUMO
An efficient photoredox/Ni dual catalytic Csp2-Csp3 cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 °C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield.
RESUMO
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.