TABLE 2.

Summary of in vitro potency and in vivo pharmacokinetic parameters of spiroindolone analogs following single oral dosing at 25 mg/kg and i.v. dosing at 5 mg/kg to female CD-1 mice^a

Compoundb	IC50 (mean ± SD) (nM) for:		Oral PK parameterc					i.v. PK parameterd
	P. falciparum NF54 (n = 3)	P. berghei GFP ANKA PbGFPCON (n = 3)	Cmax (μg/ml)	Tmax (h)	AUC0–24 (μg · h/ml)	t1/2 (h)c	F (%)	Vss (liters/kg)	CL (ml/min/kg)	t1/2 (h)
(+)-1	13 ± 2.2	242 ± 124	1.2	0.25	1.3	0.7	13	0.9	49.7	0.4
(+)-2	5.6 ± 0.9	75 ± 32	0.6	1	2.9	4.3	62	9.9	92.6	4.6
(+)-3	5.6 ± 0.7	140 ± 54	0.7	2	5.8	6.2	91	13.7	60.1	4.3
(+)-4	5.9 ± 0.9	104 ± 53	1.0	0.25	3.9	5.6	26	1.9	24.0	4.7
(+)-5	4.3 ± 0.4	88 ± 26	3.1	0.25	17.7	4.0	47	1.6	11.8	3.8
(+)-6	0.33 ± 0.06	7.5 ± 2.5	3.1	2	26.8	3.2	53	1.6	8.5	2.9
(+)-7 (KAE609)	1.2 ± 0.2	26 ± 14	0.1e	1	1.0	8.7	44	2.1	9.7	3.4
			0.25e	2	2.6	7.5	32
			3.6	1	43.3	10.0	100
			10.8e	24	186.9	9.4	100
(−)-6	105 ± 20	2,851 ± 897	5	2	68.2	7.9	78	2.8	4.2	13.2
(−)-7	210 ± 19	4,908 ± 1,445	8.3	1	107.3	9.1	92	1.3	2.6	5.6

^aIC₅₀s were determined at least three times in independent assays (16 h + 8 h of incubation periods, as indicated in Materials and Methods). i.v., intravenous.

^bThe data in parentheses indicate whether the compound is the (+) or (−) optical isomer.

^cC_max, maximum concentration of drug in plasma; T_max, time to C_max; AUC_0–24, area under the concentration-time curve from 0 to 24 h; t_1/2, elimination half-life; F, oral bioavailability.

^dV_ss, volume of distribution at steady state; CL, total systemic clearance.

^eDose proportionality PK for KAE609 at 1.5 mg/kg, 5.6, and 105 mg/kg for C_max values of 0.1, 0.25, and 10.8, respectively, using the formulation 1.1 equimolar 1 N HCl, 5 % Solutol HS15 in 50 mM (pH 3) citrate acid buffer.