Table 2.
Entry | Structure at C(3) with C(8)-ethynyl | Microsomal stability (HLM) after 2 hr | Microsomal stability (MLM) after 2 hr | |||
---|---|---|---|---|---|---|
Half-life (min) | % remaining | Half-life (min) | % remaining | |||
2 | ester | CO2CH2CH3 | < 5b | < 5.0b | 155 ± 9d | 78.0 ± 0.2d |
3 | CO2CH2CH3e | < 5b | < 5.0b | 46 ± 3 | 16.0 ± 0.4 | |
4a | CO2CH3f | 10 ± 1d | 2.0 ± 0.3d | 116 ± 13 | 41.0 ± 0.6 | |
4b | CO2CH2CH3f | < 5b | < 5.0b | < 5b | < 5.0b | |
5a | CO2CH3 | 119 ± 21d | 43.0 ± 0.4d | 216 ± 28 | 62.0 ± 0.5 | |
5b | CO2CH2CH2CH3 | < 5c | < 5.0c | 24 ± 0d | 12.0 ± 0.2d | |
5c | CO2CH(CH3)2 | 57 ± 2d | 47.0 ± 0.2d | 227 ± 16d | 83.0 ± 0.1d | |
5d | CO2C(CH3)3 | 514 ± 115d | 89.0 ± 0.2d | 196 ± 20d | 78.0 ± 0.2d | |
5f | CO2CH2CF3 | < 5a | < 5.0a | < 5b | < 5.0b | |
5g | CO2-cyclopropyl | < 5a | < 5.0a | 19 ± 2d | 11.0 ± 0.2d | |
6 | acid | COOH | 358 ± 56 | 74.0 ± 0.4 | 139 ± 11d | 54.0 ± 0.3d |
7 | thioester | COSCH2CH3 | 101 ± 19 | 28.0 ± 0.3 | 46 ± 6 | 9.0 ± 0.5 |
8a | amide | CONHCH3 | 1780 ± 39 | 92.0 ± 0.3 | 845 ± 5 | 86.0 ± 0.2 |
8b | CONHCH2CH3 | 1978 ± 50 | 93.0 ± 0.3 | 1961 ± 46 | 92.0 ± 0.3 | |
8c | CONH-cyclopropyl | 1625 ± 803d | 89.0 ± 0.4d | 320 ± 34d | 72.0 ± 0.3d | |
8d | CONHCH(CH3)2 | 107 ± 10 | 38.0 ± 0.5 | 28 ± 0 | 75.0 ± 0.3 | |
8e | CONHC(CH3)3 | 205 ± 14 | 63.0 ± 0.3 | 142 ± 9 | 52.0 ± 0.3 | |
8f | CON(CH3)2 | 59 ± 5d | 41.0 ± 0.9d | 24 ± 2d | 19.0 ± 0.9d | |
9a | 1,2,4-oxadiazole | 3-CH3 | 866 ± 213 | 86.0 ± 0.3 | 443 ± 66 | 81.0 ± 0.4 |
9b | 3-CH2CH3 | 563 ± 123 | 80.0 ± 0.4 | 213 ± 17 | 63.0 ± 0.3 | |
9c | 3-CH(CH3)2 | 2584 ± 1920 | 91.0 ± 0.3 | 500 ± 109 | 79.0 ± 0.5 | |
10 | nitrile | CN | 41 ± 5 | 9.0 ± 0.3 | 58 ± 6 | 17.0 ± 0.6 |
Compound was not detected after 10 minutes.
Compound was not detected after 20 minutes.
Compound was not detected after 30 minutes.
Compound was assessed at 1-hour incubation time.
C(8)-cyclopropyl.
C(8)-bromo. (see Supplementary material for details)