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. 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 1.

Inhibition of SK activity by spirocycloalkyl analogs.

graphic file with name nihms442143u1.jpg
No. R1 R2 X n 5 μM SK T/C a 50 μM SK T/Ca 50 μM Growth T/Cb IC50 (μM) MLM t1/2 (min)c Aq. Sol. (μM)d
1 n-Bu allyl S 1 0.84 ± 0.14 0.48 ± 0.28 0.95 ± 0.08 >50 37.2 9 ± 2
6a 4-MeOPhCH2 allyl S 1 1.00 ± 0.33 0.82 ± 0.44 1.05 ± 0.06
6b PhCH2 allyl S 1 0.74 ± 0.16 0.57 ± 0.21 0.96 ± 0.06 >50 0.6 9 ± 2
6c 4-AcNHPhCH2 allyl S 1 0.96 ± 0.46 0.74 ± 0.28 0.96 ± 0.14
6d MeOCH2CH2 allyl S 1 0.47 ± 0.28 0.29 ± 0.15 0.99 ± 0.10 6.4 9 ± 2
6e Me2NCH2CH2 allyl S 1 0.72 ± 0.12 0.52 ± 0.37 0.88 ± 0.20
6f Me allyl S 1 0.60 ± 0.19 0.42 ± 0.03 0.98 ± 0.03 19 ± 6.0 13.5 22 ± 5
7a Et allyl O 1 0.53 ± 0.23 0.14 ± 0.05 1.02 ± 0.09 14.5 ± 3.5
7b Et allyl NH 1 0.78 ± 0.47 0.56 ± 0.70 0.32 ± 0.18 9 ± 2
28 PhCH2 Et S 0 0.44 ± 0.06 0.23 ± 0.16 1.07 ± 0.04
a

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.

b

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.

c

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

d

Kinetic solubility of compound in aqueous Todd Hewitt bacterial media.