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

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• 作者：Taisuke Katoh^a ; ^{taisuke.katoh@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Takafumi Takai^a ; Takafumi Yukawa^a ; Tetsuya Tsukamoto^a ; Etsurou Watanabe^a ; Hideyuki Mototani^a ; Takeo Arita^a ; Hiroki Hayashi^a ; Hideyuki Nakagawa^a ; Michael G. Klein^b ; Hua Zou^b ; Bi-Ching Sang^b ; Gyorgy Snell^b ; Yoshihisa Nakada^a
• 关键词：PKCθ inhibitors ; 1 ; 7-Disubstituted-2 ; 2-dimethyl-2 ; 3-dihydroquinazolin-4(1H)-ones ; Inhibition of IL-2 production
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：24
• 期：11
• 页码：2466-2475
• 全文大小：2406 K

文摘

A high-throughput screening campaign helped us to identify an initial lead compound (class="boldFont">1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound class="boldFont">1 bound to PKCθ 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-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound class="boldFont">5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound class="boldFont">10. The co-crystal structure of compound class="boldFont">10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound class="boldFont">10 led us to compound class="boldFont">14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.