Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3

Figures & data

Figure 1. Docking structures of the previous JNK3 inhibitor (PDB: 3OY1) and design of the present 1-pyrimidyl-3-alkyl-5-aryl-1H-pyrazole scaffold.

Scheme 1. Synthesis of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives.

Scheme 2. Synthesis of compound 11a and 12a.

Figure 2. Comparison of docking structures of 7a and 8a at JNK3 (PDB: 3OY1).

Table 1. Enzymatic activities of 1-heteroaryl-3-alkyl-5-aryl-1H-pyrazole derivatives.

No	Ar	n	*(R/S)	R	JNK3 IC50 (μM)	No	Ar	n	*(R/S)	R	JNK3 IC50 (μM)
7a		3	S	CN	0.635	7b		3	S	CN	0.824
8a		2	R	CN	0.227	8b		2	R	CN	0.361
9a		2	S	CN	3.11	9b		2	S	CN	2.90
10a		1	-	CN	2.84	10b		1	-	CN	2.07
11a		3	S	CONH2	1.46
12a		3	S	CO2Me	0.903
7c		3	S	CN	4.60	7d		3	S	CN	7.90
8c		2	R	CN	2.18	8d		2	R	CN	4.42
9c		2	S	CN	8.57	9d		2	S	CN	3.25
10c		1	-	CN	5.58	10d		1	-	CN	NA
7e		3	S	CN	NA	7f		3	S	CN	>10
8e		2	R	CN	>10	8f		2	R	CN	7.89
9e		2	S	CN	NA	9f		2	S	CN	NA
10e		1	-	CN	NA	10f		1	-	CN	NA
Control compound					JNKI VIII^20^,^21						0.005

Table 2. Percentages of enzymatic inhibition exerted by 7a (10 μM) on 38 selected protein kinases and enzymatic activities on selected protein kinases.

Compound IC50* (M):		IC50 (nM) Control Cmpd	Control Cmpd ID
Kinase:	7a
GSK3β	3.96	2.30	Staurosporine
JNK3	0.635	5.13	JNKi VIII

We used Reaction Biology Corp. Kinase HotSpot^SM service (www.reactionbiology.com) for screening of 7a.

Figure 3. Docking structures of 8a at JNK3 (PDB: 3OY1) and 2 D-interaction map.

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