RESUMO
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Substituição de Aminoácidos , Animais , Sítios de Ligação , Ligação Competitiva , Células CHO , Bovinos , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Cricetinae , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Cinética , Modelos Moleculares , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Mutagênese Sítio-Dirigida , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Receptores de Quimiocinas/química , Receptores de Quimiocinas/genética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rodopsina/química , Rodopsina/genética , Homologia Estrutural de Proteína , TransfecçãoRESUMO
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Assuntos
Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Animais , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Cinética , Fosfolipases A/sangue , Fosfolipases A2 , Pirimidinonas/química , Coelhos , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.