RÉSUMÉ
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Sujet(s)
Conception de médicament , Interleukin-1 Receptor-Associated Kinases/antagonistes et inhibiteurs , Nicotinamide/composition chimique , Inhibiteurs de protéines kinases/composition chimique , Sites de fixation , Cristallographie aux rayons X , Évaluation préclinique de médicament , Humains , Concentration inhibitrice 50 , Interleukin-1 Receptor-Associated Kinases/métabolisme , Janus kinase 3/composition chimique , Janus kinase 3/métabolisme , Conformation moléculaire , Simulation de dynamique moléculaire , Nicotinamide/métabolisme , Inhibiteurs de protéines kinases/métabolisme , Structure tertiaire des protéines , Relation structure-activitéRÉSUMÉ
Two reaction sequences commencing with different starting materials were successfully employed for the synthesis of frondosin A analogues, including (+/-)-frondosin A dimethyl ether. Construction of the bicyclo[5.4.0]undecane core in each case was achieved through an expedient microwave-assisted tandem 5-exo cyclization--Claisen rearrangement process.