ABSTRACT
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.
Subject(s)
Drug Design , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Niacinamide/chemistry , Protein Kinase Inhibitors/chemistry , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Interleukin-1 Receptor-Associated Kinases/metabolism , Janus Kinase 3/chemistry , Janus Kinase 3/metabolism , Molecular Conformation , Molecular Dynamics Simulation , Niacinamide/metabolism , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
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.