RESUMO
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.
Assuntos
Catepsina C/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Especificidade por Substrato , Difração de Raios XRESUMO
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.
Assuntos
Descoberta de Drogas , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Formil Peptídeo/química , Humanos , Estrutura MolecularRESUMO
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.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Furanos/síntese química , Furanos/farmacologia , Receptores de Complemento/antagonistas & inibidores , Amidas/química , Animais , Derivados de Benzeno/química , Técnicas de Química Combinatória , Cães , Furanos/química , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor da Anafilatoxina C5a , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
