RÉSUMÉ
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Sujet(s)
Indoles/composition chimique , Indoles/pharmacologie , JNK Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Pyrimidines/composition chimique , Pyrimidines/pharmacologie , Cristallographie aux rayons X , Indazoles/composition chimique , Indazoles/pharmacologie , JNK Mitogen-Activated Protein Kinases/composition chimique , Phosphorylation , Relation structure-activitéRÉSUMÉ
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Sujet(s)
Protéines et peptides de signalisation intracellulaire/antagonistes et inhibiteurs , Protein-tyrosine kinases/antagonistes et inhibiteurs , Pyrazines/synthèse chimique , Pyrroles/synthèse chimique , Animaux , Lymphocytes B/effets des médicaments et des substances chimiques , Lymphocytes B/enzymologie , Protéines du sang/métabolisme , Cristallographie aux rayons X , Humains , Souris , Microsomes du foie/métabolisme , Modèles moléculaires , Structure moléculaire , Liaison aux protéines , Pyrazines/pharmacologie , Pyrazines/toxicité , Pyrroles/pharmacologie , Pyrroles/toxicité , Relation structure-activité , Syk kinaseRÉSUMÉ
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.
Sujet(s)
4-Quinolones/pharmacologie , Découverte de médicament , JNK Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/pharmacologie , 4-Quinolones/synthèse chimique , 4-Quinolones/composition chimique , Cristallographie aux rayons X , Relation dose-effet des médicaments , Humains , JNK Mitogen-Activated Protein Kinases/métabolisme , Modèles moléculaires , Structure moléculaire , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Relation structure-activitéRÉSUMÉ
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.