Discovery and optimization of 1, 7-disubstituted-2, 2-dimethyl-2, 3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors. Issue 11 (1st June 2016)

• Record Type: Journal Article
• Authors: Katoh, Taisuke; Takai, Takafumi; Yukawa, Takafumi; Tsukamoto, Tetsuya; Watanabe, Etsurou; Mototani, Hideyuki; Arita, Takeo; Hayashi, Hiroki; Nakagawa, Hideyuki; Klein, Michael G.; Zou, Hua; Sang, Bi-Ching; Snell, Gyorgy; Nakada, Yoshihisa
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 11(2016)
• Page Start: 2466
• Page End: 2475
• Publication Date: 2016-06-01
• Subjects: PKCθ inhibitors -- 1, 7-Disubstituted-2, 2-dimethyl-2, 3-dihydroquinazolin-4(1H)-ones -- Inhibition of IL-2 production; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.008
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compound1 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 compound5 . Filling the lipophilic region with a suitable lipophilic substituent boosted PKC θ inhibitory activity and led to the identification of compound10 . The co-crystal structure of compound10 bound to PKC θ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound10 led us to compound14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.