Table 1.

In Vitro and In Vivo Properties of Bumped Kinase Inhibitors

		T. gondii EC50	T. gondii EC90	TgCDPK1 IC50	Src Kinase IC50	CRL8155 CC50	HepG2 CC50	hERG IC50	Protein Binding (%)		PK Oral Dose Concentration	Cmax	AUC	Tmax	Oral Clearance	Brain/Plasma Concentration Ratio at 60 min Postdose
Central Scaffold	BKI	(nM)	(nM)	(nM)	(µM)	(µM)	(µM)	(µM)	Mouse	Human	(mg/kg)	(µM)	(µM*min)	(min)	(mL/min)
PP	1553a	60	2076	1	>10	39.5	>40	>30	90	91	10	12.8	13700	320	0.2	0.33
PP	1561a	162	1925	2	>10	>40	>40	>30	88	ND	10	7.8	16600	560	0.3	1.65
PP	1547a	173	1014	3	>10	>80	>80	>30	ND	99.9	10	5.2	850	50	0.2	ND
PrP	1660	271	4472	9	>10	>40	>40	30	99	98	10	24.9	27867	480	0.01	0.17
PrP	1649	84	1168	3	>10	>40	>40	>30	94	56	2	4.9 (24.5) c	6416 (32080)c	400	0.01	0.02
PrP	1812	114	456	11	>10	80	>80	>44	85	99.9	25	28 (11.2)c	8495 (3398)c	50	0.2	ND
AC	1673	116	1294	3	>10	>40	>40	27	95	82	10	12.9	9098	180	0.5	0.04
AC	1643b	45	849	5	>10	>40	>40	>30	88	ND	10	3.2	2679	160	0.2	0.43
AC	1597	201	1050	6	>10	>40	>40	>30	80	89	10	5.33	1694	80	0.4	0.34
AC	1748	76	596	7	>10	>40	>40	>21.5	80	84	25	38.6 (15.4)c	8530 (3412)c	70	0.4	ND
AC	1757	68	975	2	>10	>80	>80	>22.6	89	89	25	16.9 (6.8)c	11170 (4468)c	160	0.1	ND

Abbreviations: AC, 5-aminopyrazole-4-carboxamides; AUC, area under the curve; BKI, bumped kinase inhibitor; CC₅₀, 50% cytotoxicity concentration; C_max, maximum concentration; EC₅₀, 50% effective concentration; EC₉₀, 90% effective concentration; IC₅₀, 50% inhibitory concentration; ND, not determined; PK, pharmacokinetic; PP, pyrazolopyrimidines; PrP, pyrrolopyrimidines; TgCDPK1, Toxoplasma gondii calcium-dependent protein kinase 1; T_max, time at maximum concentration.

^aBKIs and some associated data previously reported [11] as compounds 31, 32, and 33.

^bBKI and some associated data previously reported [13] as compound 35.

^cValues in parenthesis are dose normalized to 10 mg/kg for direct comparison.