RESUMEN
The identification of two novel series of formyl peptide receptor 1 (FPR1) antagonists are reported, represented by methionine benzimidazole 6 and diamide 7. Both series specifically inhibited the binding of labelled fMLF to hrFPR1 and selectively antagonized FPR1 function in human neutrophils, making them useful in vitro validation tools for the target.
Asunto(s)
Descubrimiento de Drogas , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores de Formil Péptido/química , Humanos , Estructura MolecularRESUMEN
A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of (125)I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Furanos/síntesis química , Furanos/farmacología , Receptores de Complemento/antagonistas & inhibidores , Amidas/química , Animales , Derivados del Benceno/química , Técnicas Químicas Combinatorias , Perros , Furanos/química , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor de Anafilatoxina C5a , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
Asunto(s)
Catepsina C/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Relación Estructura-Actividad , Especificidad por Sustrato , Difracción de Rayos XRESUMEN
The design and synthesis of a new series of c-Jun N-terminal kinase inhibitors are reported. The novel series of substituted amino indazoles were designed based on a combination of hits from high-throughput screening and X-ray crystal structure information of the compounds crystallised into the JNK-1 ATP binding site.