Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: taisuke.katoh@takeda.com.
Taisuke
T
Katoh
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takafumi
T
Takai
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takafumi
T
Yukawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Tetsuya
T
Tsukamoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Etsurou
E
Watanabe
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hideyuki
H
Mototani
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeo
T
Arita
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hiroki
H
Hayashi
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hideyuki
H
Nakagawa
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.
Michael G
MG
Klein
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.
Hua
H
Zou
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.
Bi-Ching
BC
Sang
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.
Gyorgy
G
Snell
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Yoshihisa
Y
Nakada
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011493:Protein Kinase C
1,7-Disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones; Inhibition of IL-2 production; PKCθ inhibitors