Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Table 1

Binding affinities of pyrazolo derivatives at A₁, A_2A, A_2B, and A₃ ARs.

Pyrazolo derivatives
Type of scaffold	Compounds	𝐾𝑖, affinity (nM) or % of inhibition
		A1^a	A^b2A	A^c2B	A3^d	Refs.
Tricyclic scaffold	Pyrazolo-[4,3-e]triazolo-[1,5-c]pyrimidine
	A2A AR antagonists
	1, 8FB-PTP	3.3^e	1.2^f	ND	ND	[13]
	2	236^e	8.9^f	ND	ND	[14, 15]
	3	30.4^e	2.4^f	ND	ND	[14, 15]
	4, SCH 63390	504^e	2.4^f	ND	>10,000	[15–17]
	5, SCH 58261	121^e	2.3^f	ND	>10,000	[15–17]
	5a, [^3H]SCH 58261	—	𝐾𝐷=1 nM	—	—	[18]
	6	741^e	0.94^f	ND	>10,000	[16]
	7	444^e	1.7^f	ND	>10,000	[16]
	8, SCH 442416	1,111	0.048	>10,000	>10,000	[19]
	9, MRS5346	—	𝐾𝐷=16.5 nM	—	—	[20]
	10	4,927	4.63	>10,000	>10,000	[17]
	11	190	100	>10,000	>10,000	[17]
	12	2,160	0.22	>10,000	>10,000	[17]
	13	1	0.34	5.1	280	[21, 22]
	14	>960	0.6	ND	ND	[23]
	15, SCH 420814	>1,000	1.1	>1,700	>1,000	[23]
	A2B AR antagonists
	16	2	0.8	9	700	[24]
	17	1.6	54	27	65	[24]
	18	702	423	165	0.81	[25]
	19	1,100	800	20	300	[25]
	A3 AR antagonists
	21	1,026	1,040	245	0.6	[21]
	22, [^3H]MRE-3008-F20	—	—	—	𝐾𝐷=0.8 nM	[26]
	23	594	381	222	0.16	[22, 27–29]
	24	350	100	250	0.01	[30]
	25	235	>1,000	>1,000	>1,000	[31]
	26	562	778	>10,000^g	0.108	[32]
	27	38^h	120^i	1,500^j	4.1^k	[6, 33]
	28	610^h	>10,000^i	9,400^j	1.9^k	[6, 33]
	29	150	21	37	17	[31]
	Pyrazoloquinoline
	A3 AR antagonists
	30	32%	21%^m	ND	0.6	[34–38]
	31	45%	24%	>1,000	1	[37]
	32	464^l	35%^m	ND	2.9	[39, 40]
	33	40	1,060	ND	90.2	[39, 40]
	34	0%	9%	ND	2.1	[39, 40]
	35	>1,000	>1,000	>1,000^n	9.0	[41]
Bicyclic scaffold	Pyrazolo-[4,3-d]pyrimidinone
	A3 AR antagonist
	36	5%	1%	2%^g	1.2	[42]
	Pyrazolo-[3,4-d]pyrimidine
	A1 AR antagonists
	37	370^e	ND	ND	ND	[43, 44]
	38	0.939^e	88.3^f	ND	ND	[44]
	39	0.745^e	247^f	ND	ND	[44]
	A2A AR antagonists
	40	647	48	ND	ND	[45]
	41	468	3	ND	ND	[45]
	42	206	1	ND	ND	[45]
	A3 AR antagonists
	43	334	728.1	49.8^n	0.60	[46]
	44	1,037	3,179	53.9^n	0.18	[46]
	Pyrazolo-[1,5-a]pyridine
	A1 AR antagonists
	45, FK453	17^o	11,000^p	ND	ND	[47]
	46, FK838	120^o	5900^p	ND	ND	[48]
	47, FR166124	15^o	6200^p	ND	ND	[49]

ND: Not determined.
^{a, b, c, d}: binding affinity assay determined using recombinant cells expressing human A₁ AR, A_2A AR, A_2B AR, and A₃ AR, respectively, unless noted.
^e: binding affinity assay determined at A₁ AR in rat brain membranes.
^f: binding affinity assay determined at A_2A AR in rat striatal membranes.
^g: adenylyl cyclase assay determined using recombinant cells expressing human A_2B AR.
^{h, i, j, k}: IC₅₀ value from binding affinity assay determined with human A₁ AR, A_2A AR, A_2B AR, and A₃ AR, respectively.
^l: binding affinity assay determined at A₁ AR in bovine cerebral cortical membranes.
^m: binding affinity assay determined at A_2A AR in bovine striatal membranes.
ⁿ: IC₅₀ value from adenylyl cyclase assay determined at human A_2B AR.
^o: IC₅₀ value from binding affinity assay determined at A₁ AR in rat brain membranes.
^p: IC₅₀ value from binding affinity assay determined at A_2A AR in rat striatal membranes.