RESUMEN
Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.
Asunto(s)
Antiparasitarios/química , Descubrimiento de Drogas/tendencias , Drogas Veterinarias/química , Aminoacetonitrilo/química , Aminoacetonitrilo/farmacocinética , Animales , Antiparasitarios/farmacocinética , Combinación de Medicamentos , Macrólidos/química , Macrólidos/farmacocinética , Oxazinas/química , Oxazinas/farmacocinética , Semicarbazonas/química , Semicarbazonas/farmacocinética , Drogas Veterinarias/farmacocinéticaRESUMEN
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Asunto(s)
Naftiridinas/síntesis química , Naftiridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/fisiología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Calcio/metabolismo , Cricetinae , Cricetulus , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Indicadores y Reactivos , Articulaciones/patología , Lactonas/uso terapéutico , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Piridinas/química , Piridinas/farmacología , Ratas , Receptor del Glutamato Metabotropico 5 , Relación Estructura-Actividad , Sulfonas/uso terapéuticoRESUMEN
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Asunto(s)
Diseño de Fármacos , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Quinolinas/química , Quinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacocinética , Integrina alfaVbeta3/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacocinética , Administración Oral , Animales , Antígenos de Neoplasias , Disponibilidad Biológica , Butiratos/administración & dosificación , Perros , Evaluación Preclínica de Medicamentos , Haplorrinos , Integrinas/antagonistas & inhibidores , Estructura Molecular , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Ratas , Relación Estructura-Actividad , Tiazoles/administración & dosificaciónRESUMEN
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Antígenos de Neoplasias , Butiratos/química , Línea Celular , Humanos , Integrinas/antagonistas & inhibidores , Estructura Molecular , Oxadiazoles/química , Receptores de Vitronectina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
[reaction: see text] The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.