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Bioorg Med Chem. 2016 Jun 1;24(11):2466-75. doi: 10.1016/j.bmc.2016.04.008. Epub 2016 Apr 4.

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

Author information

1
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: taisuke.katoh@takeda.com.
2
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
3
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.

Abstract

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.

KEYWORDS:

1,7-Disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones; Inhibition of IL-2 production; PKCθ inhibitors

PMID:
27117263
DOI:
10.1016/j.bmc.2016.04.008
[Indexed for MEDLINE]

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