. Author manuscript; available in PMC: 2014 Apr 1.

Published in final edited form as: Bioorg Med Chem. 2013 Feb 1;21(7):1880–1897. doi: 10.1016/j.bmc.2013.01.046

Table 4.

Effect of N-vs. O-alkylation on GAS-SK inhibition and metabolic stability.


No.	R¹	R²	R³	5 μM SK T/C^a	50 μM SK T/C^a	50 μM Growth T/C^b	IC₅₀ (μM)	MLM t_1/2 (min)^c
19a	MeOCH₂CH₂	4-MeOPhCH₂CH₂	H	0.71 ± 0.40	0.61 ± 0.32	0.97 ± 0.07		9.4
20a	MeOCH₂CH₂	4-MeOPhCH₂CH₂	H	0.46 ± 0.37	0.24 ± 0.15	1.00 ± 0.09	5.5 ± 0.7	45.1
19b	Et	CF₃CH₂	MeO	0.78 ± 0.36	0.49 ± 0.17	1.01 ± 0.04		3.0
20b	Et	CF₃CH₂	MeO	0.51 ± 0.20	0.38 ± 0.23	0.89 ± 0.02		45.5
12a	Et	Allyl	MeO	0.10 ± 0.06	0.07 ± 0.02	0.73 ± 0.07	1.3 ± 0.6	2.3
20c	Et	Allyl	MeO	0.89 ± 0.33	0.68 ± 0.39	0.96 ± 0.02		8.3

Ratio of A₄₀₅ of SK-cleaved substrate in GAS culture treated with the indicated concentration of test compound divided by A₄₀₅ of DMSO control (see Section 5.1.1). Values are the mean of at least three experiments ± standard deviation.

Ratio of OD (600 nm) for growth of GAS in the presence of test compound divided by DMSO control. Values are the mean of at least three experiments ± standard deviation.

Half-life of parent compound during incubation with mouse liver microsomes.