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
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
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
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
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
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 , IsomerismoRESUMO
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
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
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
[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 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
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.
Assuntos
Antifúngicos/farmacologia , Aspergillus/química , Macrolídeos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida albicans/efeitos dos fármacos , Macrolídeos/química , Macrolídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacosRESUMO
A new microbial metabolite Sch 725424 (1) was isolated from the culture of Kitasatospora sp. The structure elucidation of 1 was accomplished based on NMR spectroscopic analyses as well as extensive structure elucidation of its dehydration product Sch 725428 (2). Compound 1 showed inhibitory activity against Staphylococcus aureus with MIC values 1-2 microg/ml, and also displayed weak antifungal activity against Saccharomyces cerevisiae (PM503) with an MIC 32 microg/ml.
Assuntos
Amidas/química , Amidas/metabolismo , Antibacterianos/biossíntese , Antibacterianos/química , Furanos/química , Furanos/metabolismo , Polienos/química , Polienos/metabolismo , Streptomycetaceae/metabolismo , Amidas/farmacologia , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Fermentação , Furanos/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Polienos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
A comprehensive study of nitration reaction of azatricyclic systems has been carried out. Whereas classical nitrations using KNO(3)-H(2)SO(4) at low temperatures gave nitrated products mainly at the 9-position, use of tetrabutylammonium nitrate-trifluoroacetic anhydride (TBAN-TFAA) resulted in exclusive nitration of the 3-position in the case carbamates 1, and 4-6 and the tricyclic ketone 7. These 3-nitro tricyclic derivatives have been valuable intermediates for the preparation of the very potent farnesyl protein transferase inhibitors such as the tricyclic pyridyl acetamide 32 and other new analogues.
RESUMO
Two new C-nor/D-homo corticosteroids were isolated from the filtrate of the triene carbonate intermediate during the production of betamethasone. Their structures were elucidated based on NMR spectroscopic studies and mass spectral analyses. The mechanism of formation of each of these two steroids was postulated as a Wagner-Meerwein rearrangement of the corresponding 12beta-hydroxy steroid. The new 12beta-hydroxy corticosteroid was also isolated from the fermentation process of betamethasone synthesis. Its structure was identified via NMR and mass spectroscopic studies. Treatment of the new 12beta-hydroxy corticoid with PCl(5) at low temperature provided two C-nor/D-homo compounds in a ratio of 1:1. Conversion of 12beta-hydroxy corticoid into a corresponding 12beta-mesylate followed by heating in HOAc to 110 degrees C in the presence of NaOAc produced a mixture of the rearranged products in a 1:4 ratio.
Assuntos
Corticosteroides/química , Corticosteroides/síntese química , Betametasona/análogos & derivados , Betametasona/química , Corticosteroides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Two novel antibiotics, Sch 484129 (1) and Sch 484130 (2), were isolated from the fermentation broth of a fungal culture, which was identified as a Basidiomycete. The new antibiotics were obtained by ethyl acetate extraction followed by reversed phase HPLC purification. Structure elucidation of 1 and 2 was accomplished by spectroscopic data analyses. Derivatizations of the major component 1 were performed in order to provide definitive structural information. Both components were identified as glycolipids and displayed antifungal activity against Saccharomyces and Aspergillus strains.
Assuntos
Antifúngicos/isolamento & purificação , Basidiomycota/química , Glicolipídeos/isolamento & purificação , Monossacarídeos/isolamento & purificação , Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Basidiomycota/metabolismo , Fermentação , Glicolipídeos/química , Glicolipídeos/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Monossacarídeos/química , Monossacarídeos/farmacologia , Saccharomyces/efeitos dos fármacosRESUMO
A simple isocratic reversed-phase high performance liquid chromatograghic method for the separation of pseudoephedrine and its related compounds in pharmaceutical formulations is described. The separation is achieved in less than 35 min on a C-18 column (4.6 mm I.D. x 25 cm length, 5-micrometer particle size) using a mobile phase consisting of a mixture of ammonium acetate and methanol. The results described in this report demonstrate that the method is sensitive and selective. Structural elucidation of two new pseudoephedrine degradation products is described. On the basis of structural analysis by liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-nuclear magnetic resonance spectroscopy (LC-NMR), the two newly elucidated degradation products were identified to be 2-(carboxyamino)propiophenone (molecular ion of m/z=194) and 2-formyl-2-(methylamino)-acetophenone (molecular ion of m/z=178).