17e 22.86 x 10-6 r->180 98.45 >150 <1 10 h->180 30.97 x 10-6 r->180 96.1 5.1 3.6 61 32e h->180 38b 15.51 x 10-6 r->180 98.97 <1 <1 2.5 h->180 42a 10.00 x 10-6 r->180 97.30 < 1 < 1 55 h->180 a CM culture media - Middlebrook 7H9 broth with addition of 10% albumin–dextrose–catalase – solution (Becton Dickinson), 0.2% [vol/vol] glycerol and 0.05% [vol/vol] Tween 80. A number of analogues also underwent additional DMPK (Table 14) experiments further in vitro confirming the metabolism issues detailed above. Table 14. DMPK measurements for selected analogues. In vitro Compound Aqueous Human LogD7.4 Rat Hepatocytes Solubility % PPB Microsomes CLint (µM) CLint (µL/min/106cells) (µL/min/mg) 7d 2 98.8 3.9 > 300.0 231.3 15b 0.5 98.8 3.6 > 300.0 48.9 17g < 0.5 99.5 4.7 > 300.0 183.4 17h < 0.3 99.3 > 3.2 > 300.0 91.2 17j < 0.1 99.4 4.8 > 300.0 243.4 38a 0.9 99.1 3.8 174.9 117.6 38b 1 98.6 3.6 197.4 150.1 39a 4 95.5 > 3.4 > 300.0 36.5 39b 4 95.5 > 3.4 > 300.0 36.5 42a 0.2 99.7 4 89.7 52.2
17e 22.86 x 10-6 r->180 h->180 98.45 >150 <1 10 32e 30.97 x 10-6 r->180 h->180 96.1 5.1 3.6 61 38b 15.51 x 10-6 r->180 h->180 98.97 <1 <1 2.5 42a 10.00 x 10-6 r->180 h->180 97.30 < 1 < 1 55 a CM – culture media - Middlebrook 7H9 broth with addition of 10% albumin–dextrose–catalase solution (Becton Dickinson), 0.2% [vol/vol] glycerol and 0.05% [vol/vol] Tween 80. A number of analogues also underwent additional in vitro DMPK (Table 14) experiments further confirming the metabolism issues detailed above. Table 14. In vitro DMPK measurements for selected analogues. Compound Aqueous Solubility (µM) Human % PPB LogD7.4 Microsomes CLint (µL/min/mg) Rat Hepatocytes CLint (µL/min/106cells) 7d 2 98.8 3.9 > 300.0 231.3 15b 0.5 98.8 3.6 > 300.0 48.9 17g < 0.5 99.5 4.7 > 300.0 183.4 17h < 0.3 99.3 > 3.2 > 300.0 91.2 17j < 0.1 99.4 4.8 > 300.0 243.4 38a 0.9 99.1 3.8 174.9 117.6 38b 1 98.6 3.6 197.4 150.1 39a 4 95.5 > 3.4 > 300.0 36.5 39b 4 95.5 > 3.4 > 300.0 36.5 42a 0.2 99.7 4 89.7 52.2
Quinolone%20J%20Med%20Chem%20-%20TB%20-%20final%20-%20revised.docx