Table 3.

Inhibition of SK activity by analogs with 7-, 8-, and 9-position substitution.

No.	R1	R3	5 μM SK T/Ca	50 μM SK T/Ca	50 μM Growth T/Cb	IC50 (μM)	MLM t1/2 (min)c	Aq. Sol. (μM)d
12a	Et	9-OMe	0.10 ± 0.06	0.07 ± 0.02	0.73 ± 0.07	1.3 ± 0.6	2.3	9 ± 2
12b	Et	7-OMe	0.26 ± 0.07	0.29 ± 0.18	0.28 ± 0.26
12c	Et	8-OMe	0.18 ± 0.09	0.07 ± 0.01	0.87 ± 0.19	3.1 ± 0.7	0.8	14.5 ± 3.5
12j	MeOCH2CH2	8-OMe	0.47 ± 0.25	0.25 ± 0.18	0.89 ± 0.16
12k	Allyl	8-OMe	0.33 ± 0.15	0.28 ± 0.16	0.92 ± 0.16	6.9 ± 0.3	0.6	14.5 ± 3.5
17a	Et	9-MeOCH2CH2O	0.58 ± 0.24	0.43 ± 0.15	1.02 ± 0.10
17b	Et	7-MeOCH2CH2O	0.84 ± 0.23	0.40 ± 0.21	0.94 ± 0.08
17c	Et	8-MeOCH2CH2O	0.46 ± 0.35	0.36 ± 0.41	0.85 ± 0.22
17d	Et	8-EtO2CCH2	0.64 ± 0.67	0.47 ± 0.48	1.02 ± 0.10
17e	Et	8-	0.53e	0.08e	0.41e
17f	Et	8-O-iPr	0.29 ± 0.19	0.13 ± 0.12	0.87 ± 0.23	4.1 ± 0.7		14.5 ±3.5
17g	Et	8-NCCH2O	0.45 ± 0.25	0.20 ± 0.17	0.94 ± 0.15
17h	Et	8-n-BuO	0.48 ± 0.26	0.35 ± 0.29	0.87 ± 0.10
17i	Et	8-PhCH2CH2O	0.68 ± 0.34	0.59 ± 0.55	1.01 ± 0.03
17j	Et	8-CH3(CH2)6O	1.03 ± 0.18	0.87 ± 0.12	1.05 ± 0.03
17k	Et	8-HO2CCH2O	0.96 ± 0.21	0.44 ± 0.12	0.86 ± 0.07
25	MeOCH2CH2	8-CO2Me	0.71 ± 0.30	0.58 ± 0.19	1.01 ± 0.04
26	MeOCH2CH2	8-CO2H	0.75 ± 0.36	0.70 ± 0.52	0.86 ± 0.11
27a	MeOCH2CH2	8-CONHBn	1.14 ± 0.24	0.91 ± 0.18	1.07 ± 0.02
27b	MeOCH2CH2	8-	0.84 ± 0.10	0.77 ± 0.27	0.99 ± 0.02

^aRatio 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.

^bRatio 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.

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

^dKinetic solubility of compound in aqueous Todd Hewitt bacterial media.

^eValues derived from only 1 experiment due to toxicity.