RESUMEN
We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.
Asunto(s)
Compuestos Macrocíclicos , Péptidos , Técnicas de Síntesis en Fase Sólida , Sulfuros , Sulfuros/química , Sulfuros/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/síntesis química , Péptidos/química , Péptidos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Estructura Molecular , CiclizaciónRESUMEN
Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.
Asunto(s)
Péptidos/química , Acilación , Indicadores y Reactivos , Estructura MolecularRESUMEN
A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.
RESUMEN
The design and synthesis of novel opiates are reported. Based on the message-address principle a novel class of 4,4- and 3,3-biaryl piperidines was designed and synthesized. Biological evaluation confirmed that these compounds exhibit high affinity and selectivity for the delta opioid receptor. Key structure-activity relationships that influence affinity, selectivity, functional activity and clearance are reported.
Asunto(s)
Ligandos , Piperidinas/química , Receptores Opioides delta/antagonistas & inhibidores , Animales , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Unión Proteica , Ratas , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.
