RÉSUMÉ
Pyridone-based peptidomimetic inhibitors of recombinant human Interleukin-1 beta-converting enzyme (ICE, caspase-1) with an aminomethylene ketone activating group in the P1' position are described. Several analogues with sub-nanomolar Ki's versus ICE and improved aqueous solubility are reported.
Sujet(s)
Amides/synthèse chimique , Inhibiteurs des caspases , Inhibiteurs de la cystéine protéinase/synthèse chimique , Pyridones/synthèse chimique , Amides/composition chimique , Amides/pharmacologie , Inhibiteurs de la cystéine protéinase/composition chimique , Inhibiteurs de la cystéine protéinase/pharmacologie , Humains , Cinétique , Structure moléculaire , Pyridones/composition chimique , Pyridones/pharmacologie , Protéines recombinantes/antagonistes et inhibiteurs , Solubilité , Relation structure-activitéRÉSUMÉ
Based on a tetrapeptide fragment [Pro387-Ser390] of HK we have developed a series of potent low molecular weight (5-600 Da) inhibitors of PK which are stable to the enzyme. These inhibitors show good selectivity for PK versus tissue kallikrein, thrombin and plasmin. Such inhibitors will help define the role of PK and kinins in human physiology and pathophysiology. They may also find clinical use in the treatment of diseases where kinins are important mediators.
Sujet(s)
Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Kallicréines/antagonistes et inhibiteurs , Séquence d'acides aminés , Acides aminés/analyse , Humains , Données de séquences moléculairesRÉSUMÉ
We have developed a series of novel, potent low molecular weight (4-600 Da) inhibitors of TK which were stable to cleavage by the enzyme and showed a high degree of selectivity for TK over several other serine proteases. Compound 7 (CH-2856) was found to reduce eosinophilia in a model of allergic inflammation. The effects observed in vivo provide further evidence for the involvement of TK and kinins in the pathophysiology of allergic diseases such as asthma.