Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1 H )-ones as potent and selective PKC θ inhibitors

Abstract A high-throughput screening campaign helped us to identify an initial lead compound ( 1 ) as a protein kinase C- θ (PKC θ ) inhibitor. Using the docking model of compound 1 bound to PKC θ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2 H -imidazo[4,5- b ]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5 . Filling the lipophilic region with a suitable lipophilic substituent boosted PKC θ inhibitory activity and led to the identification of compound 10 . The co-crystal structure of compound 10 bound to PKC θ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14 , which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.