Table 3.

P2 Vectors for Improved Metabolic profile and Selectivity

No.	R1	R2	TgCPLa IC50 (nM)	HsCPLb IC50 (nM)	Selectivity for TgCPLc	MLM t1/2 (min)
4	4-Fluorobenzyl		34	32	0.94	7
49	4-Fluoro-α-methylbenzyl		26	15	0.58
50*	4-Fluoro-α-methylbenzyl		92	23	0.25	5
51	4-Fluorobenzyl		310	190	0.61
52	4-Fluoro-α-methylbenzyl		143	103	0.72	4.4
53	4-Fluorobenzyl		68	160	2.4
54	4-Fluorobenzyl		17	26	1.5	3.5
55	4-Fluorobenzyl		66,800	87,500	1.3
56	4-Fluorobenzyl		26	95	3.7	15
57	4-Fluorobenzyl		3,570	66	0.018
58	4-Fluorobenzyl		110	77	0.70
59	4-Fluorobenzyl		74	60	0.81
60	4-Fluorobenzyl		1,900	1,190	0.63
61	4-Fluorobenzyl		326	969	2.9
62	4-Fluorobenzyl		181	1,200	6.7	>60
63	4-Fluorobenzyl		1,200	960	0.80
64	4-Fluorobenzyl		400	94	0.25
65	4-Fluorobenzyl		49	170	3.5	3.5
66	4-Fluorobenzyl		630	370	0.58
67	2-Nitrobenzyl		3,970	1,240	0.3
68	4-Fluorobenzyl		1,600	517	0.33

^a,bIC₅₀ for Toxoplasma gondii Cathepsin L (TgCPL) or human Cathepsin L (HsCPL). Values are mean of at least 3 independent experiments with SEM typically < 30%.

^cSelectivity for Toxoplasma gondii Cathepsin L as defined by the ratio HsCPL IC₅₀/TgCPL IC₅₀.

^*S1 morpholine group replaced with oxetan-3-amine.