RESUMEN
N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide is a potent C-C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtree's catalyst). The labeling pattern in the product was studied with liquid chromatography-mass spectrometry, time-of-flight mass spectrometry, and (3) H-NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration.
Asunto(s)
Radiofármacos/síntesis química , Receptores CCR1/antagonistas & inhibidores , Sulfonamidas/síntesis química , Tritio/química , Valina/análogos & derivados , Sulfonamidas/química , Valina/síntesis química , Valina/químicaRESUMEN
Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.
Asunto(s)
Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/metabolismo , Profármacos/síntesis química , Ticlopidina/análogos & derivados , Fenómenos Biológicos , Clopidogrel , Humanos , Microsomas Hepáticos/efectos de los fármacos , Piperidinas/química , Inhibidores de Agregación Plaquetaria/química , Profármacos/química , Estereoisomerismo , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/metabolismoRESUMEN
Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.
Asunto(s)
Carbamatos/química , Compuestos Heterocíclicos con 2 Anillos/química , Piridinas/síntesis química , Compuestos de Azufre/química , Agua/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Piridinas/químicaRESUMEN
A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Imidazoles/química , Imidazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Sistema Enzimático del Citocromo P-450/análisis , Imidazoles/síntesis química , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Bencimidazoles , Línea Celular , Humanos , Concentración 50 Inhibidora , Piridonas , Relación Estructura-ActividadRESUMEN
A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Fosfotransferasas/antagonistas & inhibidores , Animales , Baculoviridae/enzimología , Línea Celular , Proliferación Celular/efectos de los fármacos , Indicadores y Reactivos , Ratones , Modelos Moleculares , Piridonas/farmacología , Relación Estructura-Actividad , Timidina/metabolismoRESUMEN
Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas the development of agents that selectively stimulate neurotrophin signaling has proven to be difficult, compounds have been identified that potentiate neurotrophin 3 (NT-3)-mediated activation of trk A. In the present studies, we extend those initial observations to identify compounds that also potentiate NT-3-mediated activation of trk B. Compound potentiation of NT-3 was observed using several readouts of transfected and endogenous trk receptor activity, including trk receptor phosphorylation, mitogen-activated protein kinase phosphorylation, reporter assay activity (beta-lactamase and luciferase), cell survival and neurite extension assays. Studies using chimeric trk receptors demonstrated that the extracellular domain is essential for compound potentiation and rule out interaction with intracellular signaling molecules as a mechanism of compound activity. Thus, the present studies demonstrate that trk B receptor activity can be potentiated by small-molecule compounds via the extracellular domain of the receptor and provide reagents for further evaluating the role of NT-3-mediated trk A and trk B activity in vivo.
Asunto(s)
Neurotrofina 3/farmacología , Receptor trkB/agonistas , Animales , Western Blotting , Línea Celular , Proliferación Celular/efectos de los fármacos , Cricetinae , ADN Complementario , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación , Ratas , Receptor trkB/genética , Receptor trkB/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. METHODS: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. RESULTS: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. CONCLUSIONS: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Profármacos/farmacología , Animales , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/síntesis química , Camptotecina/farmacocinética , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Humanos , Irinotecán , Masculino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3H , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Piridinas/síntesis química , Piridonas/síntesis química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Receptor de Insulina/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Camptotecina/farmacología , Carbazoles/síntesis química , Glucósidos/síntesis química , Indoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Glucósidos/química , Glucósidos/farmacología , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Irinotecán , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Topoisomerasa I , Trasplante HeterólogoRESUMEN
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Asunto(s)
Carbazoles/síntesis química , Carbono/química , Inhibidores Enzimáticos/síntesis química , Flúor/química , Glicósidos/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Hidrocarburos Fluorados/síntesis química , Indoles/síntesis química , Inhibidores de Topoisomerasa I , Animales , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glicósidos/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Hidrocarburos Fluorados/química , Indoles/química , Leucemia P388 , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Glucósidos/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Glucósidos/química , Glucósidos/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Solubilidad , Relación Estructura-Actividad , Agua , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacocinética , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Administración Oral , Animales , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Compuestos Aza/química , Compuestos Aza/farmacología , Glicósidos/química , Indenos , Inyecciones Intravenosas , Ratones , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Aldehídos/síntesis química , Aldehídos/química , Aldehídos/farmacología , Alquilación , Diterpenos , Hongos/efectos de los fármacos , Hidrólisis , Indicadores y Reactivos , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Relación Estructura-ActividadRESUMEN
Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.
Asunto(s)
Antifúngicos/metabolismo , Antifúngicos/farmacología , Antifúngicos/química , Biotransformación , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Diterpenos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Nocardia/metabolismo , EstereoisomerismoRESUMEN
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Oxazepinas/síntesis química , Oxazepinas/farmacología , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Enlace de Hidrógeno , Indenos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.