RESUMO
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aß40-42, compared to their parent compounds.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/química , Inibidores Enzimáticos/química , Sulfonas/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Flúor/química , Flúor/farmacologia , Humanos , Estrutura Molecular , Oxirredução , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
Assuntos
Alcaloides/síntese química , Furanos/síntese química , Naftalenos/síntese química , Piperidinas/síntese química , Inibidores da Agregação Plaquetária/síntese química , Agregação Plaquetária/efeitos dos fármacos , Receptor PAR-1/antagonistas & inibidores , Administração Oral , Alcaloides/farmacocinética , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Descoberta de Drogas , Furanos/farmacocinética , Humanos , Macaca fascicularis , Naftalenos/farmacocinética , Piperidinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Trombina/metabolismoRESUMO
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
Assuntos
Antipsicóticos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Pirazóis/farmacologia , Quinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Modelos Químicos , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.
Assuntos
Ácidos Aristolóquicos/síntese química , Proteína Quinase CDC2/antagonistas & inibidores , Pirazóis/síntese química , Quinolinas/síntese química , Ácidos Aristolóquicos/química , Ácidos Aristolóquicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The 70% aqueous methanolic extract of the Chinese plant Aristolochia manshuriensis was found to contain two novel substituted phenanthrene compounds, SCH 546909 (1), and another phenanthrene glycoside (2). The structures of 1 and 2 were established based on NMR studies. They were identified as inhibitors of the CDK2 enzyme. Compound 1 was found to be a potent inhibitor of the CDK2 enzyme with an IC50 of 140 nM, whereas compound 2 was found to be less active with an IC50 of >10 microM.
Assuntos
Antineoplásicos/farmacologia , Aristolochia/química , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Glicosídeos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Extratos Vegetais/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Glicosídeos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Metanol/química , Estrutura Molecular , Água/químicaRESUMO
Use of liquid chromatography/tandem mass spectrometric (LC/MS(n)) molecular fingerprinting is systematically demonstrated as a very effective tool for rapid structural elucidation of pharmaceutical impurities through a case study in which three isomers of betamethasone sodium phosphate (BSP) were rapidly identified as degradants formed due to the D-homoannular ring expansion of the steroid core structure of BSP in the solid state. The rapid structural elucidation of these degradants was achieved by matching or closely matching the UV profiles, molecular weights, and more importantly the fragmentation patterns obtained from the LC/MS(n) (n = 1 to 3) analysis of their enzyme-catalyzed hydrolytic products, respectively, with those of a D-homoannular isomer of betamethasone available in our LC/MS(n) molecular fingerprint database. This strategy of using LC/MS(n) molecular fingerprinting to obtain high-confidence structures of unknown species is then validated by structure verification through one- (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments.
Assuntos
Betametasona/análogos & derivados , Cromatografia Líquida/métodos , Contaminação de Medicamentos , Preparações Farmacêuticas/química , Espectrometria de Massas em Tandem/métodos , Betametasona/química , IsomerismoAssuntos
Antibacterianos/química , Aspergillus/química , Benzopiranos/química , Antibacterianos/biossíntese , Antibacterianos/farmacologia , Antifúngicos/biossíntese , Antifúngicos/química , Antifúngicos/farmacologia , Benzopiranos/farmacologia , Candida albicans/efeitos dos fármacos , Fermentação , Espectroscopia de Ressonância Magnética , Conformação Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
Four new caryophyllene derivatives, Sch 725432 (1), Sch 601253 (2), Sch 601254 (3), and Sch 725434 (4), were isolated from the fungal fermentation broth of Chrysosporium pilosum by reversed-phase HPLC purification. The structure elucidation of trioxygenated caryophyllenes 1-4 was accomplished on the basis of spectroscopic data interpretation. Sch 725434 (4) possesses a dihydrofuran-3-one ring, forming a tricyclic ring skeleton, which represents an unprecedented ring skeleton for the caryophyllene-type of sesquiterpenes. Compounds 1-4 were evaluated for their antifungal activity.
Assuntos
Chrysosporium/química , Saccharomyces cerevisiae/efeitos dos fármacos , Sesquiterpenos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Investigation of unexpected levels of impurities in Intron product has revealed the presence of low levels of impurities leached from the silicone tubing (Rehau RAU-SIK) on the Bosch filling line. In order to investigate the effect of these compounds (1a, 1b and 2) on humans, they were isolated identified and synthesized. They were extracted from the tubing by stirring in Intron placebo at room temperature for 72 h and were enriched on a reverse phase CHP-20P column, eluting with gradient aqueous ACN and were separated by HPLC. Structural elucidation of 1a, 1b and 2 by MS and NMR studies demonstrated them to be halogenated biphenyl carboxylic acids. The structures were confirmed by independent synthesis. Levels of extractable impurities in first filled vials of actual production are estimated to be in the range of 0.01-0.55 microg/vial for each leached impurity. Potential toxicity of these extractables does not represent a risk for patients under the conditions of clinical use.
Assuntos
Contaminação de Medicamentos , Interferon-alfa/química , Interferon-alfa/isolamento & purificação , Compostos Orgânicos/química , Silicones/química , Soluções Tampão , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/métodos , Liofilização , Humanos , Concentração de Íons de Hidrogênio , Interferon alfa-2 , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Estrutura Molecular , Pós , Controle de Qualidade , Proteínas Recombinantes , Temperatura , Fatores de TempoRESUMO
Four diastereomers of betamethasone 17-deoxy-20-hydroxy-21-oic acid were found to be degradants of betamethasone sodium phosphate when the latter was stressed by heat under the solid state. The structure elucidation of these four diastereomers was achieved by a combination of LC-MS(n) (n = 1-3), various 1D and 2D NMR experiments, and mechanistic consideration of potential degradation pathways. A mechanism for the formation of the four degradants has been proposed, which involves hydration of a key intermediary degradant, betamethasone enol aldehyde, followed by intramolecular Cannizzaro reaction. The proposed mechanism is supported by a model reaction which converted betamethasone enol aldehyde into the four diastereomeric degradants in good yields, albeit in solution chemistry.
Assuntos
Betametasona/análogos & derivados , Glucocorticoides/química , Betametasona/química , Catálise , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Temperatura Alta , Isomerismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Químicos , Espectrofotometria UltravioletaRESUMO
Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
Assuntos
Alcaloides/síntese química , Furanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Isoquinolinas/síntese química , Naftalenos/síntese química , Piperidinas/síntese química , Inibidores da Agregação Plaquetária/síntese química , Piridinas/síntese química , Receptor PAR-1/antagonistas & inibidores , Administração Oral , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Disponibilidade Biológica , Plaquetas/metabolismo , Furanos/farmacocinética , Furanos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Bioassay-guided fractionation of an active fraction from an extract of a marine starfish, Novodinia antillensis, led to the isolation and identification of two new saponins, Sch 725737 (1) and Sch 725739 (2). Compound 1 was identified as the NaV1.8 inhibitor with IC(50) of approximately 9 microM. The purification and the structure elucidation of these two saponins are described.
Assuntos
Saponinas/química , Estrelas-do-Mar/química , Esteroides/química , Animais , Sequência de Carboidratos , Espectroscopia de Ressonância Magnética , Potenciais da Membrana/efeitos dos fármacos , Saponinas/isolamento & purificação , Saponinas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/isolamento & purificação , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Esteroides/isolamento & purificação , Esteroides/farmacologiaRESUMO
A novel fungal secondary metabolite, Sch 213766 was isolated from the fungal fermentation broth of Chaetomium globosum as the chemokine receptor CCR-5 inhibitor and shown to be the methyl ester of the previously described tetramic acid Sch 210972 on the basis of UV, MS and NMR spectral data analyses. Sch213766 exhibited an IC(50) value of 8.6 muM in the CCR-5 receptor in vitro binding assay.
Assuntos
Antagonistas dos Receptores CCR5 , Chaetomium/metabolismo , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/metabolismo , Chaetomium/crescimento & desenvolvimento , Meios de Cultivo Condicionados/metabolismo , Fermentação , Éteres Metílicos/química , Éteres Metílicos/isolamento & purificação , Éteres Metílicos/metabolismo , Éteres Metílicos/farmacologiaRESUMO
Data from two-dimensional (2D) NMR experiments were used to identify the reaction products resulting from the opening of pyroglutamates with isocyanates or thioisocyanates. The reaction has the potential to produce compounds that would have very similar one-dimensional proton ((1)H) or carbon-13 ((13)C) NMR spectra. Careful analysis of (1)H--(1)H COSY, (1)H--(1)H NOESY, and HMBC data, including chemical shifts and coupling constants, were used to distinguish correctly between carbamoyl-2-pyrrolidinone, hydantoin, and perhydro-1,3-diazepine-2,4-dione type structures that could result from this reaction. This work describes their preparation and subsequent identification using 2D NMR spectroscopy, and includes complete (13)C assignments of the reaction products. The 2D NMR techniques and analysis described here can be applied successfully to other synthetic reactions with the potential to produce isomeric products.
Assuntos
Hidantoínas/química , Espectroscopia de Ressonância Magnética/métodos , Isótopos de Carbono , Hidantoínas/síntese química , Espectroscopia de Ressonância Magnética/normas , Estrutura Molecular , Prótons , Padrões de Referência , Sensibilidade e Especificidade , EstereoisomerismoRESUMO
Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis. The major component 2 demonstrated a potent inhibitory activity of IC(50) = 79 nM in the CCR-5 receptor in vitro binding assay.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Chaetomium/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Arizona , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Folhas de Planta/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
Assuntos
Alcaloides/química , Furanos/química , Lactonas/química , Naftalenos/química , Piperidinas/química , Receptor PAR-1/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Receptor PAR-1/metabolismo , Relação Estrutura-AtividadeRESUMO
A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 microg/ml, respectively.
Assuntos
Antifúngicos/isolamento & purificação , Aspergillus/metabolismo , Resorcinóis/isolamento & purificação , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Resorcinóis/química , Resorcinóis/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacosRESUMO
[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.
RESUMO
A new hydrogenated azaphilone Sch725680 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was achieved based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 64 microg/ml, respectively.
Assuntos
Antibacterianos/química , Antifúngicos/química , Aspergillus/química , Benzopiranos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Aspergillus/metabolismo , Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Candida albicans/efeitos dos fármacos , Fermentação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Saccharomyces cerevisiae/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacosRESUMO
A new macrolide Sch725674 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 32 microg/ml, respectively.