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

[Display omitted] A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be e...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2016-06, Vol.24 (11), p.2466-2475
Main 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
Format: Article
Language:English
Subjects:
1,7-Disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones
Animals
Dose-Response Relationship, Drug
Drug Discovery
Female
Humans
Inhibition of IL-2 production
Mice
Mice, Inbred BALB C
Molecular Structure
PKCθ inhibitors
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - metabolism
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacology
Structure-Activity Relationship
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Summary:[Display omitted] A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 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 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.04.008