RESUMO
Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.
Assuntos
Quelantes/química , Inibidores Enzimáticos/química , Metaloproteinases da Matriz/metabolismo , Sequência de Bases , Quelantes/metabolismo , Cristalografia por Raios X , Primers do DNA , Dimerização , Inibidores Enzimáticos/metabolismo , Inibidores de Metaloproteinases de Matriz , Zinco/químicaRESUMO
A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Sítios de Ligação , Quelantes/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Metaloproteinase 12 da Matriz , Metaloendopeptidases/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Zinco/químicaRESUMO
The synthesis and SAR studies of spiroquinazolinones as novel PDE7 inhibitors are discussed. The best compounds from the series displayed nanomolar inhibitory affinity and were selective versus other PDE isoenzymes.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Quinazolinas/síntese química , Compostos de Espiro/síntese química , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7 , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoenzimas/metabolismo , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Solubilidade , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7 , Humanos , Isoenzimas/metabolismo , Inibidores de Fosfodiesterase/química , Relação Estrutura-Atividade , Tiadiazóis/químicaRESUMO
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacocinética , Tiadiazóis/farmacocinética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7 , Isoenzimas/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented.