RESUMEN
A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase.
Asunto(s)
Aminopiridinas/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Fructosa-Bifosfatasa/antagonistas & inhibidores , Administración Oral , Sitio Alostérico , Aminopiridinas/química , Animales , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Fructosa-Bifosfatasa/química , Fructosa-Bifosfatasa/metabolismo , Humanos , Concentración 50 Inhibidora , Hígado/enzimología , Ratones , Estructura MolecularRESUMEN
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/química , Quinolizinas/química , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Humanos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Quinolizinas/metabolismo , Quinolizinas/farmacología , Ratas , Ratas ZuckerRESUMEN
Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fructosa-Bifosfatasa/antagonistas & inhibidores , Hipoglucemiantes/química , Compuestos de Sulfonilurea/química , Tiazoles/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Fructosa-Bifosfatasa/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Ratones , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Tetrakis(dimethylamino)ethylene (TDAE 1), has been exploited for the first time as a mild reagent for the reduction of arenediazonium salts to aryl radical intermediates through a single electron transfer (SET) pathway. Cyclization of the aryl radicals produced in this way led, in appropriate substrates, to syntheses of indolines and indoles. Cascade radical cyclizations of aryl radicals derived from arenediazonium salts are also reported. The relative ease of removal of the oxidized by-products of TDAE from the reaction mixture makes the methodology synthetically attractive.
RESUMEN
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Inhibidores de la Dipeptidil-Peptidasa IV , Glicoproteínas/antagonistas & inhibidores , Piperidinas/química , Inhibidores de Proteasas/química , Adenosina Desaminasa/química , Dipeptidil Peptidasa 4/química , Glicoproteínas/química , Humanos , Piperidinas/síntesis química , Piperidinas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Conformación Proteica , Relación Estructura-ActividadRESUMEN
[reaction: see text] A novel, mild, ecofriendly protocol for the deoxygenation of epoxides to alkenes using indium metal and indium(I) chloride or ammonium chloride in alcohol has been developed. It was necessary for the presence of good radical-stabilizing groups adjacent to the oxirane ring for the deoxygenation reaction to occur. It is proposed that this reaction occurs through an SET process with indium as an electron donor.
RESUMEN
The first examples of highly enantioselective [2,3]-sigmatropic rearrangements of acyclic allylic ammonium ylids are reported. Thus, a range of N-{2'-[(N'-allyl-N',N'-dialkyl)ammonium]}acetyl camphor sultams undergo rearrangement at 0 degrees C in DME solution with high diastereofacial control (up to 99:1 dr) to give allylglycines in generally high yield. The power of the method has been demonstrated in a rapid and efficient synthesis of (R)-allyl glycine.
Asunto(s)
Compuestos Alílicos/química , Glicina/análogos & derivados , Compuestos de Amonio Cuaternario/química , Compuestos Alílicos/síntesis química , Alilglicina/síntesis química , Alilglicina/química , Glicina/síntesis química , Glicina/químicaRESUMEN
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.
Asunto(s)
Anticoagulantes/química , Anticoagulantes/farmacología , Factor VIIa/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Tromboplastina/antagonistas & inhibidores , Administración Oral , Animales , Anticoagulantes/síntesis química , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Glicina/análogos & derivados , Glicina/química , Humanos , Estructura Molecular , Ratas , Inhibidores de Serina Proteinasa/síntesis químicaRESUMEN
A ring-contractive and highly diastereoselective [2,3]-sigmatropic rearrangement occurs when N-methyl-1,2,3,6-tetrahydropyridine is treated with sub-stoichiometric amounts of copper or rhodium salts, in the presence of ethyl diazoacetate, giving ethyl cis-N-methyl-3-ethenyl proline (4).