RESUMEN
Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds for ß-lactamase inhibition. We achieved a concise and collective synthesis of 2-thio-substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong inhibitory activities against serine ß-lactamases and acceptable solution stabilities for clinical development.
Asunto(s)
Octanos , Inhibidores de beta-Lactamasas , Antibacterianos , Compuestos de Azabiciclo/farmacología , Pruebas de Sensibilidad Microbiana , Octanos/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-LactamasasRESUMEN
The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N, N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine ß-secretase inhibitor 2.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Dietilaminas/farmacología , Inhibidores Enzimáticos/farmacología , Flúor/farmacología , Tiazinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ciclización , Dietilaminas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Flúor/química , Humanos , Estructura Molecular , Tiazinas/síntesis química , Tiazinas/químicaRESUMEN
Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/farmacología , Pirroles/farmacología , Receptores Purinérgicos P2X3/efectos de los fármacos , Administración Oral , Disponibilidad Biológica , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Neuralgia/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Relación Estructura-ActividadRESUMEN
Accumulation of Aß peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. ß-Secretase (BACE1) is a key enzyme responsible for producing Aß peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p Ka lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aß reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Oxazinas/química , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Secretasas de la Proteína Precursora del Amiloide/química , Animales , Ácido Aspártico Endopeptidasas/química , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Canal de Potasio ERG1/metabolismo , Cobayas , Humanos , Células de Riñón Canino Madin Darby , Ratones Endogámicos C57BL , Ratones Noqueados , Oxazinas/farmacología , Inhibidores de Proteasas/farmacocinética , Relación Estructura-ActividadRESUMEN
ß-Secretase (BACE1) has an essential role in the production of amyloid ß peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aß reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxazinas/química , Oxazinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Humanos , Simulación del Acoplamiento Molecular , Oxazinas/metabolismo , Oxazinas/farmacocinética , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución TisularRESUMEN
Atlantic spiny lobsters support major fisheries in northeastern Brazilian waters and in the Caribbean Sea. To avoid reduction in diversity and elimination of distinct stocks, understanding their population dynamics, including structuring of populations and genetic diversity, is critical. We here explore the potential of using the hypervariable domain in the control region of the mitochondrial DNA as a genetic marker to characterize population subdivision in spiny lobsters, using Panulirus argus as the species model. The primers designed on the neighboring conserved genes have amplified the entire control region (approx. 780 bases) of P. argus and other closely related species. Average nucleotide and haplotype diversity within P. argus were found to be high, and population structuring was hypothesized. The data suggest a division of P. argus into genetically different phylogeographic groups. The hypervariable domain seems to be useful for determining genetic differentiation of geographically distinct stocks of P. argus and other Atlantic spiny lobsters.