Table 3. PD Activity for Lead MEK Inhibitor (8) and XL518 (1).

				tumorb				brainb
		plasmab		2 h		24 h		2 h		24 h
compd	dosea	concn 2 h	concn 24 h	concn	p-ERK (%)	concn	p-ERK (%)	concn	p-ERK (%)	concn	p-ERK (%)
8	30	2.4	0.03	7.36	27	26.85	44	0.73	23	1.24	17
4c		0.01	0.21	<LQ		<LQ		<LQ		<LQ
1	5		<LQ			0.53	16			<LQ	8
1	10		0.1			1.99	45			<LQ	7
1	20		0.1			3.59	75			<LQ	2
1	100		0.12			22.85	87			0.22	0

^aSingle oral dosage in MDA-MB-231T tumor bearing mice in mg/kg.

^bParent drug and metabolite (4) concentrations given in units of μM. p-ERK (T202/Y204) reported as % inhibition.

^cMetabolite (4) measured on administration of parent (8).