RÉSUMÉ
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Sujet(s)
JNK Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Pyrimidines/composition chimique , Pyrimidines/pharmacologie , Triazoles/composition chimique , Triazoles/pharmacologie , Animaux , Cristallographie aux rayons X , Conception de médicament , Humains , JNK Mitogen-Activated Protein Kinases/métabolisme , Modèles moléculaires , Inhibiteurs de protéines kinases/synthèse chimique , Pyrimidines/synthèse chimique , Rats , Relation structure-activité , Triazoles/synthèse chimiqueRÉSUMÉ
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.