RESUMEN
A radical mediated C-H functionalization of 3,6-dichloropyridazine using primary alcohols, t-BuOOH, and TiCl3 to access alkoxy pyridazines is described. This transformation is conducted open to air and on gram scale. A subsequent cyclization step can then be employed to efficiently access diversely substituted tetrahydropyridopyridazines with multiple functional handles.
Asunto(s)
Radicales Libres/química , Piridazinas/síntesis química , Piridinas/síntesis química , Ciclización , Estructura Molecular , Piridazinas/química , Piridinas/químicaRESUMEN
Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).
Asunto(s)
Amidas/química , Benzodiazepinas/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Indoles/química , Oxazepinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Amidas/metabolismo , Amidas/farmacología , Animales , Azepinas/química , Benzamidas/química , Benzamidas/metabolismo , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacología , Sitios de Unión , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Proteínas HSP90 de Choque Térmico/metabolismo , Indoles/metabolismo , Indoles/farmacología , Células de Riñón Canino Madin Darby , Simulación del Acoplamiento Molecular , Oxazepinas/metabolismo , Oxazepinas/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismoRESUMEN
A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/ß inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/ß inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/ß selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/ß inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.
Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Enfermedad de Huntington/tratamiento farmacológico , Animales , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/química , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and ß is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/ß appear to strongly influence isoform selectivity. The rational design of HSP90α/ß inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.
Asunto(s)
Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Enfermedades Neurodegenerativas/tratamiento farmacológico , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Isoformas de Proteínas/antagonistas & inhibidoresRESUMEN
Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.
Asunto(s)
Aldehídos/química , Ciclopropanos/química , Nitrilos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The preparation of the diastereomerically pure beta-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1.