RESUMEN
An efficient synthesis of α-amino-γ-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU-mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin-susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.
RESUMEN
NR1/NR2A is a subtype of N-methyl-d-aspartate receptors (NMDARs), which are glutamate and glycine-gated Ca(2+)-permeable channels highly expressed in the central nervous system. A high-throughput screening (HTS) campaign using human osteosarcoma (U-2 OS) cells transiently transduced with NR1/NR2A NMDAR subunits, tested in a specifically designed fluorometric imaging plate reader (FLIPR)/Ca(2+) assay, identified sulfonamide derivative series, exemplified by 3-chloro-4-fluoro-N-[(4-{[2-(phenylcarbonyl)hydrazino]carbonyl}phenyl)methyl]benzenesulfonamide (compound 1) and thiodiazole derivative N-(cyclohexylmethyl)-2-({5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio)acetamide (compound 13) as novel NR1/NR2A receptor antagonists. Compounds 1 and 13 displayed submicromolar and micromolar potency at NR1/NR2A receptor, respectively, although they did not show activity at NR2B-containing receptor up to 50 µM concentration. Addition of 1 mM glycine, but not 1 mM l-glutamate, was able to surmount compound 1 and 13 inhibitory effects in FLIPR NR1/NR2A assay. However, compounds 1 and 13 displaced a glutamate site antagonist [(3)H]d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid ([(3)H]CGP 39653) to a greater extent than the glycine site antagonist [(3)H]3-[(E)-2-carboxy-2-phenylethenyl]-4,6-dichloro-1H-indole-2-carboxylic acid ([(3)H]MDL 105,519), in rat brain cortex binding assay. Results of FLIPR cell-based, electrophysiological, and biochemical binding assays suggest that compounds 1 and 13 are the prototypes of novel classes of NMDAR ligands, which to the best of our knowledge are the first selective antagonists at NR1/NR2A over NR1/NR2B receptor, and might constitute useful tools able to elucidate the relative role of the NR2A subunit in physiological and pathological conditions.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Unión Competitiva , Señalización del Calcio/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/metabolismo , Corteza Cerebral/citología , Evaluación Preclínica de Medicamentos/métodos , Antagonistas de Aminoácidos Excitadores/química , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Fluorometría/métodos , Ácido Glutámico/farmacología , Glicina/farmacología , Células HEK293 , Humanos , Masculino , Estructura Molecular , N-Metilaspartato/farmacología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , TransfecciónRESUMEN
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
Asunto(s)
Imidazolidinas/química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Química Orgánica/métodos , Química Farmacéutica/métodos , Antagonistas de los Receptores de Dopamina D2 , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Tomografía de Emisión de Positrones , Ratas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Relación Estructura-Actividad , PorcinosRESUMEN
One of the still unresolved problems in parallel synthesis is the availability of a general and rapid method for the transformation of a primary amine into the corresponding secondary amine without the issue of polyalkylation. Following the Fukuyama method, which is based on the alkylation of o-nitrobenzenesulfonamides, followed by removal of the sulfonyl group, we have developed a simple protocol which can be easily applied to parallel synthesis making use of supported reagents and scavengers. To verify the robustness of the method, a small representative array of secondary amines have been prepared. Moreover, taking advantage of the possibility to use different supported reagents in the same pot, we also prepared, starting from primary amines, a series of differently substituted tertiary amines.