Background
Methods
Materials
Molecular property descriptors
Instrumentation and sample analysis
Ionization constants
Partition coefficients
Solubility in biorelevant media
Permeability
Solubility limited absorbable dose calculations
In vitro protein binding
Media sources
Protein binding via ultracentrifugation (UC)
Protein binding via rapid equilibrium dialysis (RED)
Blood to plasma partitioning
In vitro metabolism in human liver microsomes
Cytochrome P450 inhibition
Results
Molecular properties
Compound | Mass (Da) | cLog P | HBD/HBA | tPSA (Å2) | FRB | AROM | Fsp3 |
---|---|---|---|---|---|---|---|
Development compounds | |||||||
AQ-13 | 291.82 | 3.00 | 1/3 | 30.6 | 7 | 2 | 0.44 |
Artemisone | 401.52 | 2.21 | 0/7 | 74.3 | 1 | 0 | 1.00 |
DSM265 | 415.33 | 5.68 | 1/4 | 55.1 | 4 | 3 | 0.21 |
DSM421 | 358.28 | 3.34 | 1/5 | 68.0 | 4 | 3 | 0.29 |
ELQ300 | 475.85 | 7.20 | 1/4 | 56.8 | 6 | 4 | 0.13 |
Ferroquine | 433.76 | 3.54 | 1/3 | 30.6 | 7 | 2 | 0.26 |
JPC3210 | 398.45 | 4.51 | 2/3 | 49.7 | 6 | 2 | 0.48 |
KAF156 | 411.46 | 3.07 | 2/4 | 77.8 | 4 | 3 | 0.27 |
KAE609 | 390.24 | 4.17 | 3/2 | 56.9 | 0 | 3 | 0.21 |
M5717 | 462.57 | 3.53 | 1/5 | 58.9 | 7 | 3 | 0.41 |
MMV048 | 393.38 | 2.70 | 1/5 | 85.9 | 4 | 3 | 0.11 |
MMV052 | 525.73 | 5.91 | 2/6 | 73.8 | 4 | 1 | 0.81 |
MMV253 | 465.58 | 4.23 | 2/8 | 88.2 | 6 | 3 | 0.50 |
NPC1161B | 434.36 | 4.86 | 2/4 | 71.0 | 8 | 3 | 0.32 |
OZ277 | 392.54 | 3.11 | 2/5 | 84.4 | 4 | 0 | 0.95 |
OZ439 | 469.62 | 5.44 | 0/6 | 49.4 | 5 | 1 | 0.79 |
P218 | 360.41 | − 0.04 | 3/8 | 138 | 10 | 2 | 0.39 |
SJ733 | 468.41 | 3.64 | 1/4 | 86.1 | 5 | 3 | 0.17 |
Tafenoquine | 463.50 | 4.97 | 2/5 | 80.3 | 10 | 3 | 0.38 |
TDD-E209 | 501.64 | 6.06 | 0/6 | 50.6 | 5 | 1 | 0.79 |
Legacy compounds | |||||||
Amodiaquine | 355.87 | 3.80 | 2/4 | 49.6 | 6 | 3 | 0.25 |
Desethylamodiaquine | 327.81 | 2.99 | 3/4 | 61.8 | 5 | 3 | 0.17 |
Artemether | 298.38 | 3.48 | 0/5 | 46.2 | 1 | 0 | 1.00 |
Artesunate | 384.43 | 3.10 | 1/7 | 103 | 5 | 0 | 0.89 |
Atovaquone | 366.84 | 5.00 | 1/3 | 57.2 | 2 | 2 | 0.27 |
Azithromycin | 749.00 | 2.44 | 5/13 | 183 | 7 | 0 | 0.97 |
Chloroquine | 319.88 | 3.93 | 1/3 | 30.6 | 8 | 2 | 0.50 |
Chlorproguanil | 288.18 | 2.99 | 5/5 | 87.3 | 2 | 1 | 0.27 |
Clindamycin | 424.98 | 1.04 | 4/6 | 104 | 7 | 0 | 0.94 |
Dapsone | 248.30 | 1.27 | 2/4 | 86.2 | 2 | 2 | 0.00 |
Dihydroartemisinin | 284.35 | 2.84 | 1/5 | 57.2 | 0 | 0 | 1.00 |
Doxycyclin | 444.44 | − 3.34 | 6/9 | 186 | 2 | 1 | 0.41 |
Halofantrine | 500.43 | 8.06 | 1/2 | 24.7 | 11 | 3 | 0.46 |
Lumefantrine | 528.94 | 9.19 | 1/2 | 24.7 | 10 | 3 | 0.33 |
Mefloquine | 378.32 | 4.11 | 2/3 | 49.7 | 4 | 2 | 0.47 |
Naphthoquine | 409.96 | 5.22 | 3/4 | 61.8 | 5 | 3 | 0.38 |
Piperaquine | 535.52 | 5.27 | 0/6 | 41.2 | 6 | 4 | 0.38 |
Primaquine | 259.35 | 1.64 | 2/4 | 61.8 | 6 | 2 | 0.40 |
Proguanil | 253.73 | 2.38 | 5/5 | 87.3 | 2 | 1 | 0.27 |
Cycloguanil | 251.72 | 1.70 | 2/5 | 81.6 | 1 | 1 | 0.27 |
Pyrimethamine | 248.71 | 2.75 | 2/4 | 79.1 | 2 | 2 | 0.17 |
Pyronaridine | 518.06 | 4.22 | 2/7 | 79.0 | 7 | 4 | 0.38 |
Quinine | 324.42 | 2.51 | 1/4 | 46.8 | 4 | 2 | 0.45 |
Sulfadoxine | 310.33 | 0.58 | 2/7 | 114 | 4 | 2 | 0.17 |
Sulfamethoxazole | 253.28 | 0.79 | 2/4 | 95.4 | 2 | 2 | 0.10 |
Ionization and partitioning properties
Compound | Calculated pKa | Measured pKaa | Calculated Log D7.4 | Measured Log D
7.4
b
|
---|---|---|---|---|
Ionized or partially ionized bases at physiological pH | ||||
Cycloguanil | 10.5 (B) | 11.4 ± 0.3 (B) | − 1.80 | − 1.10 |
Doxycyclin | 9.13 (B), 3.35 (A), 9.98 (A) | CNDe | − 0.75 | − 0.20 |
Pyronaridine | 7.65 (B), 6.39 (B), 5.20 (B), 10.1 (A) | CNDe | 5.61 | 0.23 |
Proguanil | 10.0 (B), 6.64 (B) | CNDc | 0.21 | 0.27 |
Primaquine | 9.92 (B), 3.88 (B) | 10.2 ± 0.12 (B), 3.3 ± 0.02 (B) | 0.40 | 0.54 |
Chloroquine | 9.86 (B), 7.25 (B) | 9.9 ± 0.1 (B), 8.4 ± 0.1 (B) | 2.42 | 0.93 |
Chlorproguanil | 9.79 (B), 6.29 (B) | CNDc | 0.84 | 1.10 |
Azithromycin | 8.72 (B), 7.63 (B) | CNDe | 1.64 | 1.10 |
AQ-13 | 9.63 (B), 7.28 (B) | 7.6 ± 0.2 (B) | 1.89 | 1.30 |
Desethylamodiaquine | 10.3 (B), 6.21 (B), 8.14 (A) | 8.5 ± 0.05 (B), 7.1 ± 0.01 (B) | 3.51 | 1.30 |
Quinine | 7.95 (B), 3.87 (B) | 8.5 ± 0.05 (B), 4.2 ± 0.03 (B) | 1.99 | 1.80 |
Clindamycin | 7.44 (B) | 7.1 ± 0.07 (B) | 1.62 | 1.90 |
KAF156 | 8.08 (B), 3.83 (B) | 8.4 ± 0.06 (B), 4.5 ± 0.02 (B) | 1.80 | 2.06 |
M5717 | 8.67 (B), 6.23 (B), 2.54 (B), 10.9 (A) | 8.7 ± 0.11 (B), 6.8 ± 0.04 (B)g | 2.49 | 2.50 g |
OZ277 | 9.38 (B) | 8.9 ± 0.16 (B) | 1.28 | 2.60 |
Mefloquine | 8.52 (B) | 8.5 ± 0.04 (B) | 2.66 | 2.70 |
Amodiaquine | 7.95 (B), 6.25 (B), 10.3 (A) | 7.0 ± 0.02 (B) | 4.27 | 2.95 |
NPC1161B | 9.94 (B), 3.61 (B) | 9.3 ± 0.03 (B), 6.0 ± 0.01 (B) | 3.24 | CNDf |
Ferroquine | 8.08 (B), 6.74 (B) | 8.4 ± 0.06 (B), 7.5 ± 0.02 (B) | 5.41 | 3.39 |
Naphthoquine | 8.48 (B), 6.48 (B), 10.7 (A) | CNDd | 5.36 | 4.18 |
Tafenoquine | 10.0 (B), 4.00 (B) | 8.7 ± 0.09 (B), 6.0 ± 0.10 (B) | 2.61 | 4.24 |
MMV253 | 8.03 (B), 4.63 (B), 3.03 (B), 2.52 (B) | 8.0 ± 0.03 (B), 5.5 ± 0.03 (B) | 3.76 | 4.42 |
MMV052 | 8.75 (B) | 8.3 ± 0.06 (B) | 4.58 | 5.40 |
Piperaquine | 7.60 (B), 5.93 (B), 5.15 (B), 4.36 (B) | CNDe | 5.59 | CNDf |
Halofantrine | 9.20 (B) | CNDd | 5.78 | CNDf |
TDD-E209 | 7.40 (B) | CNDd | 5.84 | CNDf |
Lumefantrine | 8.66 (B) | CNDd | 7.34 | CNDf |
Ionized acids at physiological pH | ||||
Sulfadoxine | 2.01 (B), 6.40 (A) | 6.2 ± 0.01 (A) | − 0.28 | − 0.780 |
Sulfamethoxazole | 6.15 (A) | 6.1 ± 0.01 (A) | − 0.25 | − 0.780 |
Artesunate | 4.51 (A) | 4.7 ± 0.04 (A) | − 0.38 | − 0.120 |
Atovaquone | 4.28 (A) | CNDd | 2.58 | 5.30 |
Zwitterionic or partially zwitterionic at physiological pH | ||||
P218 | 7.22 (B), 4.26 (A) | 7.3 ± 0.003 (B), 4.9 ± 0.002 (A) | 0.49 | 0.080 |
JPC3210 | 8.20 (B), 10.5 (A) | 5.3 ± 0.04 (A) | 5.42 | 5.30 |
Neutral at physiological pH | ||||
Dapsone | 3.06 (B), 2.18 (B) | CNDe | 0.97 | 0.86 |
Dihydroartemisinin | NA | NA | 2.16 | 2.30 |
DSM421 | 3.04 (B) | CNDc | 3.51 | 2.36 g |
Pyrimethamine | 6.57 (B) | 6.9 ± 0.10 (B) | 2.47 | 2.41 |
MMV048 | 4.18 (B) | 4.0 ± 0.07 (B) | 2.81 | 2.50 |
Artemisone | 5.22 (B) | CNDc | 1.36 | 2.82 |
Artemether | NA | NA | 2.80 | 3.70 |
SJ733 | 3.16 (B), 10.7 (A) | 4.1 ± 0.03 (B) | 3.34 | 3.90 |
DSM265 | 3.23 (B) | CNDc | 4.59 | 4.03 |
KAE609 | 3.95 (B), 10.7 (A), 10.1 (A) | 5.1 ± 0.02 (B) | 4.36 | CNDf |
OZ439 | 6.38 (B) | CNDd | 5.03 | CNDf |
ELQ300 | NA | NA | 5.28 | CNDf |
Solubility
Compound | Solubility (µg/mL)/(µM)a | |||
---|---|---|---|---|
FaSSGF (1 h) | FaSSIF-V2 (5–6 h) | FeSSIF-V2 (5–6 h) | PBS7.4 (5–6 h) | |
Ionized or partially ionized bases at physiological pH | ||||
Cycloguanil | > 2000/> 7950 | > 2000/> 7950 | 533/2120 | > 2000/> 7950 |
Doxycyclin | > 2000/> 4500 | > 2000/> 4500 | > 2000/> 4500 | > 2000/> 4500 |
Pyronaridine | > 2000/> 3800 | > 2000/> 3860 | > 2000/> 3800 | 357/689 |
Proguanil | > 2000/> 7880 | > 2000/> 7880 | > 2000/> 7880 | > 2000/> 7880 |
Primaquine | > 2000/> 7700 | > 2000/> 7700 | > 2000/> 7700 | > 2000/> 7700 |
Chloroquine | > 2000/> 6250 | > 2000/> 6250 | > 2000/> 6250 | > 2000/> 6250 |
Chlorproguanil | > 2000/> 6940 | 1100/3810 | 1670/5780 | 1420/4930 |
Azithromycin | 1180/1570 | 1440/1930 | > 2000/> 2670 | > 2000/> 2670 |
AQ-13 | > 2000/> 6850 | > 2000/> 6850 | > 2000/> 6850 | 1480/5070 |
Quinine | 1925/5930 | 1960/6050 | 1930/5930 | 806/2480 |
Clindamycin | > 2000/> 4700 | > 2000/> 4700 | > 2000/> 4700 | > 2000/> 4700 |
KAF156 | > 2000/> 4850 | 1600/3880 | > 2000/> 4850 | 560/1360 |
M5717 | > 3000/> 6490b | > 3000/> 6490b | > 3000/> 6486b | > 3000/> 6490b |
OZ277 | > 2000/> 5000 | > 2000/> 5100 | > 2000/> 5000 | 198/504 |
Mefloquine | 740/1960 | 584/1540 | > 2000/> 5200 | 290/767 |
Amodiaquine | > 2000/> 5620 | 1120/3150 | > 2000/> 5620 | 26.3/73.9 |
NPC1161B | 1520/3500 | 19.9/45.8 | > 2000/> 4600 | 5.44/12.5 |
Ferroquine | > 2000/> 4600 | 320/738 | > 2000/> 4600 | 4.9/11 |
Naphthoquine | > 2000/> 4880 | 410/1000 | 941/2300 | 28.5/69.5 |
Tafenoquine | > 2000/> 2800 | 15.8/34.1 | 1310/2820 | 18.3/39.5 |
MMV253 | > 2000/> 4300 | 569/1220 | > 2000/> 4300 | 19.0/40.8 |
MMV052 | 13.0/24.7 | 1140/2170 | > 2000/> 3800 | 49.6/94.3 |
Piperaquine | > 2000/> 3700 | 103/192 | 60.7/113 | < 0.5/< 0.9 |
Halofantrine | 12.7/25.4 | 69.9/140 | 739/1480 | < 0.05/< 0.1 |
TDD-E209 | 211/421 | 87.2/174 | > 2000/> 4000 | 0.056/0.112 |
Lumefantrine | 12.6/23.8 | 0.063/0.119 | 14.4/27.2 | < 0.05/< 0.1 |
Ionized acids at physiological pH | ||||
Sulfadoxine | 324/1040 | 858/2770 | 474/1530 | > 1900/> 6400 |
Sulfamethoxazole | 758/2990 | > 2000/> 7900 | > 2000/> 7900 | > 2000/> 7900 |
Artesunate | 321/835 | 1690/4390 | 1720/4490 | 1680/4370 |
Atovaquone | 0.26/0.71 | 1.83/4.99 | 6.41/17.5 | < 0.05/< 0.1 |
Zwitterionic or partially zwitterionic at physiological pH | ||||
P218 | > 2000/> 5550 | 408/1130 | 525/1460 | 1070/2960 |
JPC3210 | 213/535 | 7.60/19.1 | 131/329 | 0.800/2.01 |
Neutral at physiological pH | ||||
Dapsone | 946/3810 | 323/1300 | 423/1700 | 227/914 |
Dihydroartemisinin | 140/492 | 159/559 | 246/865 | 130/457 |
DSM421 | 116/324b | 92.7/259b | 119/332b | 85.5/239 |
Pyrimethamine | > 2000/> 8000 | 111/446 | 120/483 | 43/175 |
MMV048 | 1200/3040 | 6.73/17.1 | 7.47/19.0 | 4.52/11.5 |
Artemisone | 89.1/222 | 115/286 | 278/692 | 86.1/214 |
Artemether | 95/320 | 166/556 | 1040/3480 | 109/365 |
SJ733 | > 2000/> 4270 | 101/216 | 119/254 | 115/246 |
DSM265 | 6.84/16.5b | 5.12/12.3b | 27.6/66.5b | 2.04/4.9 |
KAE609 | 1540/3940 | 111/284 | 1240/3180 | 30.4/77.9 |
OZ439 | 79.0/168 | 40.6/87 | 526/1120 | 0.085/0.181 |
ELQ300 | 0.929/1.95 | 0.524/1.10 | 0.065/0.137 | 0.102/0.214 |
Permeability
Compound | Matrix | A–B mass bal (%) | A–B P
app
a
(10−6 cm/s) | B–A mass bal (%) | B–A P
app
a
(10−6 cm/s) | Efflux ratio |
---|---|---|---|---|---|---|
Ionized or partially ionized bases at physiological pH | ||||||
Cycloguanil | Buffer | 100 | 1.2 ± 0.070 | 100 | 0.77 ± 0.05 | 0.7 |
Doxycyclin | Buffer | 99 | 3.4 ± 0.23 | 110 | 4.2 ± 0.29 | 1.2 |
Pyronaridine | Plasma | 63 | 16 ± 2.2 | 87 | 41 ± 3.0 | 2.6 |
Proguanil | Buffer | 82 | 3.5 ± 0.75 | 95 | 7.9 ± 0.51 | 2.3 |
Primaquine | Buffer | 66 | 29 ± 4.5 | 99 | 34 ± 1.5 | 1.2 |
Chloroquineb | Plasma | 61 | 16 ± 2.5 | 110 | 22 ± 4.6 | 1.4 |
Chlorproguanil | Plasma | 79 | 19 ± 3.0 | 100 | 61 ± 7.4 | 3.2 |
Azithromycin | Buffer | 98 | 0.37, 0.38 | 87 | 13 ± 3.9 | 33 |
AQ-13 | Plasma | 54 | 25 ± 2.3 | 92 | 32 ± 0.8 | 1.2 |
Quinineb | Buffer | 70 | 39 ± 5.0 | 92 | 40 ± 4.5 | 1.0 |
Clindamycin | Buffer | 75 | 17 ± 1.1 | 92 | 48 ± 9.1 | 2.8 |
KAF156 | Plasma | 86 | 47 ± 7.6 | 96 | 230 ± 17 | 4.9 |
M5717 | Buffer | 60 | 34 ± 2.6 | 81 | 39 ± 7.6 | 1.1 |
OZ277 | Plasma | 67 | 42 ± 2.8 | 100 | 70 ± 0.38 | 1.7 |
Mefloquineb | Plasma | 70 | 180 ± 20 | 86 | 150 ± 10 | 0.83 |
Amodiaquineb | Plasma | 81 | 90 ± 8.3 | 88 | 63 ± 9.6 | 0.7 |
NPC1161B | Plasma | 76 | > 300 | 97 | > 300 | – |
Ferroquine | Plasma | 66 | 32 ± 6.8 | 110 | 24 ± 4.1 | 0.8 |
Naphthoquineb | Plasma | 72 | 230 ± 32 | 94 | 180 ± 10 | 0.78 |
Tafenoquine | Plasma | 79 | > 300 | 110 | v300 | – |
MMV253 | Plasma | 84 | 150 ± 29 | 94 | 150 ± 23 | 1.0 |
MMV052 | Plasma | 77 | > 300 | 110 | > 300 | – |
Piperaquineb | Plasma | 100 | > 300 | 100 | > 300 | – |
Halofantrineb | Plasma | 83 | > 300 | 87 | > 300 | – |
TDD-E209 | Plasma | 93 | > 300 | 100 | > 300 | – |
Lumefantrine | Plasma | 110 | CND | 110 | CND | CND |
Ionized acids at physiological pH | ||||||
Sulfadoxine | Buffer | 93 | 15 ± 2.5 | 110 | 23 ± 2.8 | 1.6 |
Sulfamethoxazole | Buffer | 96 | 4.5 ± 0.29 | 100 | 5.9 ± 0.26 | 1.3 |
Artesunate | Buffer | 81 | 3.4, 2.9 | 84 | 2.8 ± 0.48 | 0.9 |
Atovaquone b | Plasma | 99 | > 300 | 97 | > 300 | – |
Zwitterionic or partially zwitterionic at physiological pH | ||||||
P218 | Buffer | 96 | 0.71 ± 0.04 | 100 | 15 ± 1.7 | 21 |
JPC3210 | Plasma | 97 | > 300 | 100 | > 300 | – |
Neutral at physiological pH | ||||||
Dapsone | Buffer | 86 | 45 ± 7.3 | 98 | 56 ± 1.3 | 1.2 |
Dihydroartemisinin | Buffer | 85 | 50 ± 2.3 | 91 | 49 ± 1.2 | 1.0 |
DSM421c | Buffer | 70 | 33 ± 2.5 | 98 | 46 | 1.4 |
Pyrimethamine | Buffer | 75 | 60 ± 5.6 | 100 | 59 ± 2.9 | 1.0 |
MMV048 | Buffer | 82 | 41 ± 2.1 | 98 | 53 ± 1.9 | 1.3 |
Artemisone | Buffer | 98 | 58.8, 64.5 | 99 | 47 ± 1.7 | 0.8 |
Artemether | Buffer | 73 | 39.1, 46.3 | 95 | 42 ± 5.6 | 1.0 |
SJ733 | Buffer | 93 | 14.0, 13.4 | 99 | 50 ± 2.0 | 3.6 |
DSM265 | Buffer | 83 | 52.4, 69.7 | 93 | 49 ± 5.1 | 0.9 |
KAE609 | Plasma | 93 | > 300 | 98 | > 300 | – |
OZ439 | Plasma | 91 | > 300 | 110 | > 300 | – |
ELQ300 | Plasma | 99 | > 300 | 110 | > 300 | – |
Solubility limited absorbable dose
Compound | Permeability | Solubility/dose | |||
---|---|---|---|---|---|
Predicted human Peff (10−4 cm/s) | Permeability classificationa | An | Ssi (µg/mL) | SLAD (mg) | |
Ionized or partially ionized bases at physiological pH | |||||
Doxycyclin | 0.70 | Intermediate | 1.0 | > 2000 | > 1000 |
Pyronaridine | 1.4 | High | 1.6 | > 2000 | > 1610 |
Proguanil | 0.71 | Intermediate | 1.0 | > 2000 | > 1000 |
Primaquine | 3.0 | High | 3.6 | > 2000 | > 3560 |
Chloroquine | 1.4 | High | 1.6 | > 2000 | > 1620 |
Chlorproguanil | 1.5 | High | 1.8 | 1100 | 998 |
Azithromycin | 0.16 | Low | 1.0 | 1440 | 720 |
AQ-13 | 1.9 | High | 2.2 | > 2000 | > 2250 |
Quinine | 3.7 | High | 4.4 | 1960 | 4280 |
Clindamycin | 2.1 | High | 2.5 | > 2000 | > 2530 |
KAF156 | 2.9 | High | 3.5 | 1600 | 2780 |
M5717 | 3.4 | High | 4.0 | > 3000 | > 6050 |
OZ277 | 2.7 | High | 3.2 | > 2000 | > 3240 |
Mefloquine | 7.7 | High | 9.2 | 584 | 2690 |
Amodiaquine | 4.7 | High | 5.6 | 1120 | 3130 |
Ferroquine | 2.2 | High | 2.7 | 320 | 426 |
Naphthoquine | 9.2 | High | 11 | 410 | 2250 |
Tafenoquine | 11 | High | 13 | 15.8 | 105 |
MMV253 | 6.8 | High | 8.1 | 569 | 2300 |
MMV052 | 11 | High | 13 | 1140 | 7580 |
Piperaquine | 11 | High | 13 | 103 | 685 |
Halofantrine | 11 | High | 13 | 69.9 | 466 |
TDD-E209 | 11 | High | 13 | 87.0 | 579 |
Lumefantrine | CND | CND | CND | CND | CND |
Ionized acids at physiological pH | |||||
Sulfadoxine | 1.9 | High | 2.2 | 858 | 959 |
Sulfamethoxazole | 0.85 | Intermediate | 1.0 | > 2000 | > 1000 |
Artesunate | 0.66 | Intermediate | 1.0 | 1690 | 845 |
Atovaquone | 11 | High | 13 | 1.83 | 12 |
Zwitterionic or partially zwitterionic at physiological pH | |||||
P218 | 0.24 | Low | 1.0 | 408 | 204 |
JPC3210 | 11 | High | 13 | 7.60 | 51 |
Neutral at physiological pH | |||||
Dapsone | 4.1 | High | 4.9 | 323 | 786 |
Dihydroartemisinin | 4.4 | High | 5.2 | 159 | 413 |
DSM421 | 3.3 | High | 3.9 | 93.0 | 182 |
Pyrimethamine | 4.9 | High | 5.9 | 111 | 326 |
MMV048 | 3.8 | High | 4.5 | 6.70 | 15 |
Artemisone | 5.0 | High | 6.0 | 115 | 345 |
Artemether | 3.9 | High | 4.7 | 166 | 388 |
SJ733 | 1.8 | High | 2.2 | 101 | 109 |
DSM265 | 4.8 | High | 5.7 | 5.10 | 14 |
KAE609 | 11 | High | 13 | 111 | 738 |
OZ439 | 11 | High | 13 | 40.6 | 270 |
ELQ300 | 11 | High | 13 | 0.520 | 3 |
Binding and whole blood partitioning
Compound | Fraction unbound ± SD | |||
---|---|---|---|---|
Human Plasmaa | Albumaxa | 10% FCS in DMEMa | HLMa | |
Ionized or partially ionized bases at physiological pH | ||||
Cycloguanil | 0.75 ± 0.040 | 0.88 ± 0.057 | 0.94 ± 0.064 | 0.72 ± 0.083 |
Doxycyclin | 0.23 ± 0.090b | 0.41 ± 0.023 | 0.44 ± 0.070 | 0.93 ± 0.045 |
Pyronaridine | 0.090 ± 0.012b | 0.69 ± 0.023 | Not assessed | 0.29 ± 0.018 |
Proguanil | 0.34 ± 0.010 | 0.80 ± 0.021 | Not assessed | 0.33 ± 0.014 |
Primaquine | 0.26 ± 0.023 | 0.96 ± 0.056 | 0.78 ± 0.025 | 0.56 ± 0.050 |
Chloroquine | 0.54 ± 0.048 | 0.97 ± 0.069 | Not assessed | 0.50 ± 0.032 |
Chlorproguanil | 0.10 ± 0.0070 | 0.50 ± 0.020 | Not assessed | 0.052 ± 0.004 |
Azithromycin | 0.34, 0.35b | 0.76 ± 0.065 | Not assessed | 0.70 ± 0.060 |
AQ-13 | 0.43 ± 0.022 | 0.85 ± 0.028 | Not assessed | 0.66 ± 0.048 |
Desethylamodiaquine | 0.17 ± 0.0020 | 0.75 ± 0.074 | Not assessed | not assessed |
Quinine | 0.37 ± 0.040b | 0.69 ± 0.090 | Not assessed | 0.57 ± 0.036 |
Clindamycin | 0.19 ± 0.011 | 0.65 ± 0.066 | Not assessed | 0.67 ± 0.084 |
KAF156 | 0.069 ± 0.013b | 0.38 ± 0.017 | 0.477 ± 0.032 | 0.14 ± 0.0060 |
M5717 | 0.24 ± 0.0020b | 0.55 ± 0.041 | 0.638 ± 0.065 | 0.50 ± 0.041 |
OZ277 | 0.086 ± 0.0080 | 0.29 ± 0.021 | Not assessed | 0.044 ± 0.0050 |
Mefloquine | 0.015 ± 0.0010b | 0.27 ± 0.019 | Not assessed | 0.050 ± 0.0060 |
Amodiaquine | 0.089 ± 0.0080 | 0.67 ± 0.033 | Not assessed | 0.91 ± 0.094 |
NPC1161B | 0.00074 ± 0.00016c | 0.035 ± 0.0020 | 0.043 ± 0.004 | CNDe |
Ferroquine | 0.041 ± 0.0010c | 0.52 ± 0.031 | 0.364 ± 0.026 | 0.27 ± 0.032 |
Naphthoquine | 0.018 ± 0.0010c | 0.27 ± 0.035 | Not assessed | 0.21 ± 0.015 |
Tafenoquine | 0.00070 ± 0.00017c | CNDe | 0.038 ± 0.001 | 0.0020 ± 0.00030 |
MMV253 | 0.017 ± 0.00020c | 0.48 ± 0.026 | Not assessed | 0.11 ± 0.017 |
MMV052 | 0.00040 ± 0.00010c | 0.014 ± 0.0010 | Not assessed | 0.0010 ± 0.00010 |
Piperaquine | 0.0003 ± 0.0001c | 0.019 ± 0.0040 | 0.092 ± 0.0030 | 0.013 ± 0.0020 |
Halofantrine | < 0.0001c | 0.0080 ± 0.0010 | Not assessed | 0.0020 ± 0.00020 |
TDD-E209 | < 0.0001c | 0.0070 ± 0.0010 | Not assessed | 0.00030 ± 0.000010 |
Lumefantrine | < 0.0001c | CNDe | Not assessed | CNDe |
Ionized acids at physiological pH | ||||
Sulfadoxine | 0.036 ± 0.0010 | 0.50 ± 0.030 | 0.86 ± 0.044 | 0.93 ± 0.086 |
Sulfamethoxazole | 0.32 ± 0.024 | 0.67 ± 0.120 | 0.87 ± 0.058 | 1.00 ± 0.033 |
Artesunate | 0.27 ± 0.0080d | 0.14 ± 0.0070d | 0.72 ± 0.026 | CNDd |
Atovaquone | < 0.0001c | CNDe | CNDe | ~ 0.0020 |
Zwitterionic or partially zwitterionic at physiological pH | ||||
P218 | 0.13 ± 0.013 | 0.41 ± 0.022 | 0.684 ± 0.017 | 0.88 ± 0.041 |
JPC3210 | 0.0028 ± 0.00020c | 0.21 ± 0.012 | 0.227 ± 0.012 | 0.029 ± 0.0030 |
Neutral at physiological pH | ||||
Dapsone | 0.27 ± 0.019 | 0.63 ± 0.11 | Not assessed | 0.86 ± 0.059 |
Dihydroartemisinin | 0.21 ± 0.010d | 0.34 ± 0.018d | Not assessed | 0.87 ± 0.10d |
DSM421 | 0.039 ± 0.007 | 0.43 ± 0.020 | 0.615 ± 0.043 | 0.77 ± 0.065f |
Pyrimethamine | 0.095 ± 0.0010b | 0.46 ± 0.090 | 0.48 ± 0.034 | 0.54 ± 0.097 |
MMV048 | 0.11 ± 0.0070b | 0.46 ± 0.022 | 0.653 ± 0.060 | 0.61 ± 0.014 |
Artemisone | 0.12 ± 0.0060 | 0.46 ± 0.013 | Not assessed | 0.44 ± 0.024 |
Artemether | 0.038 ± 0.0090c | 0.46 ± 0.039 | Not assessed | 0.50 ± 0.052 |
SJ733 | 0.085 ± 0.012c | 0.40 ± 0.040 | Not assessed | 0.58 ± 0.069 |
DSM265 | 0.0018 ± 0.00010c | 0.18 ± 0.0050f | 0.366 ± 0.041 | 0.28 ± 0.0070f |
KAE609 | 0.0016 ± 0.00010c | 0.044 ± 0.0040 | Not assessed | 0.019 ± 0.0010 |
OZ439 | < 0.0001c | 0.010 ± 0.0010 | Not assessed | 0.0010 ± 0.00010 |
ELQ300 | 0.00010 ± 0.000010c | CNDe | 0.001 ± 0.001 | 0.002 ± 0.00010 |
Compound | B/Pa | Haematocrit (Gender) |
---|---|---|
Ionized or partially ionized bases at physiological pH | ||
Cycloguanil | 0.71 ± 0.07 | 0.48 (M) |
Doxycyclin | 0.78 ± 0.06 | 0.43 (M) |
Pyronaridine | 9.0 ± 0.83 | 0.48 (M) |
Proguanil | 3.30 ± 0.14 | 0.46 (M) |
Primaquine | 0.82 ± 0.07 | 0.44 (M) |
Chloroquine | 3.5 ± 0.09 | 0.42 (F) |
Chlorproguanil | 3.3 ± 0.38 | 0.43 (M) |
Azithromycin | 1.6 ± 0.19 | 0.48 (M) |
AQ-13 | 3.15 ± 0.20 | 0.42 (M) |
Desethylamodiaquine | 3.26 ± 0.35 | 0.50 (M) |
Quinine | 0.67 ± 0.02 | 0.44 (M) |
Clindamycin | 0.61 ± 0.04 | 0.42 (M) |
KAF156 | 1.3 ± 0.02 | 0.42 (F) |
M5717 | 1.3 ± 0.02 | 0.42 (F) |
OZ277 | 1.10 ± 0.10 | 0.46 (M) |
Mefloquine | 1.1 ± 0.07 | ~ 0.43 (M) |
Amodiaquine | 1.1 ± 0.18 | ~ 0.43 (M) |
NPC1161B | 1.09 ± 0.07 | 0.44 (M) |
Ferroquine | 1.6 ± 0.15 | ~ 0.43 (M) |
Naphthoquine | 1.14 ± 0.10 | ~ 0.43 (M) |
Tafenoquine | 1.3 ± 0.04 | ~ 0.43 (M) |
MMV253 | 1.0 ± 0.05 | ~ 0.43 (M) |
MMV052 | 1.6 ± 0.14 | ~ 0.43 (M) |
Piperaquine | 0.57 ± 0.05 | ~ 0.43 (M) |
Halofantrine | 0.68 ± 0.06 | 0.43 (M) |
TDD-E209 | 0.51 ± 0.08 | 0.44 (M) |
Lumefantrine | 0.48 ± 0.09 | 0.48 (M) |
Ionized acids at physiological pH | ||
Sulfadoxine | 0.57 ± 0.03 | 0.46 (M) |
Sulfamethoxazole | 0.65 ± 0.07 | 0.43 (M) |
Artesunate | CNDb | 0.44 (M) |
Atovaquone | 0.52 ± 0.03 | 0.44 (M) |
Zwitterionic or partially zwitterionic at physiological pH | ||
P218 | 0.56 ± 0.03 | ~ 0.43 (M) |
JPC3210 | 0.54 ± 0.04 | ~ 0.43 (M) |
Neutral at physiological pH | ||
Dapsone | 1.1 ± 0.06 | 0.43 (M) |
Dihydroartemisinin | CNDb | 0.42 (M) |
DSM421 | 0.53 ± 0.03 | 0.44 (M) |
Pyrimethamine | 0.84 ± 0.03 | 0.43 (M) |
MMV048 | 0.77 ± 0.03 | 0.42 (F) |
Artemisone | CNDb | 0.44 (M) |
Artemether | CNDb | 0.42 (M) |
SJ733 | 0.72 ± 0.02 | 0.42 (F) |
DSM265 | 0.54 ± 0.02 | 0.44 (M) |
KAE609 | 0.66 ± 0.04 | 0.42 (F) |
OZ439 | 0.78 ± 0.05 | 0.44 (M) |
ELQ300 | 0.53 ± 0.05 | 0.44 (M) |
In vitro metabolism
Compound | HLM CLint (µL/min/mg)a | Unbound CLint (µL/min/mg) |
---|---|---|
Ionized or partially ionized bases at physiological pH | ||
Cycloguanil | < 7b | < 9.72c |
Doxycyclin | < 7b | < 7.53c |
Pyronaridine | 8.6 | 29.7 |
Proguanil | < 7b | < 21.2c |
Primaquine | 7.70 | 13.8 |
Chloroquine | < 7b | < 14c |
Chlorproguanil | < 7b | < 135c |
Azithromycin | < 7b | < 10c |
AQ-13 | < 7b | < 10.6c |
Desethylamodiaquine | 13.3 | CNDd |
Quinine | 16.5 | 28.9 |
Clindamycin | 32.0 | 47.8 |
KAF156 | 14.7 | 105 |
M5717 | 11.1 | 22.2 |
OZ277 | < 7b | < 159 |
Mefloquine | < 7b | < 140c |
Amodiaquine | 308 | 339 |
NPC1161B | < 7b | CND |
Ferroquine | 29.2 | 108 |
Naphthoquine | 14.4 | 68.6 |
Tafenoquine | < 7b | < 3500c |
MMV253 | 13.2 | 120 |
MMV052 | 13.0 | 13,000 |
Piperaquine | 20.1 | 1540 |
Halofantrine | 26.9 | 13,500 |
TDD-E209 | 25.5e | 85,000 |
Lumefantrine | < 7b | CNDd |
Ionized acids at physiological pH | ||
Sulfadoxine | < 7b | < 7.53 |
Sulfamethoxazole | < 7b | < 7.00 |
Artesunate | 146 | CNDd |
Atovaquone | < 7b | < 3500c |
Zwitterionic or partially zwitterionic at physiological pH | ||
P218 | < 7b | < 7.95c |
JPC3210 | 9.50 | 328 |
Neutral at physiological pH | ||
Dapsone | < 7b | < 8.14c |
Dihydroartemisinin | 16.6 | 19.1 |
DSM421 | < 7b | < 9.09c |
Pyrimethamine | < 7b | < 13c |
MMV048 | < 7b | < 11.5c |
Artemisone | 97.7 | 222 |
Artemether | 163 | 326 |
SJ733 | 142 | 245 |
DSM265 | < 7b,e | < 25c |
KAE609 | 24.1 | 1270 |
OZ439 | 72.1 | 72,100 |
ELQ300 | < 7b | < 3500c |
CYP inhibition
Compound | IC50 (µM) (% inhibition at max conc)/Ki (µM) | |||||
---|---|---|---|---|---|---|
CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | CYP3A4 (test) | CYP3A4 (midaz) | |
Ionized or partially ionized bases at physiological pH | ||||||
Cycloguanil | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.0/3.7 | > 20 (nmi) | > 20 (nmi) |
Doxycyclin | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (22%) | > 20 (nmi) |
Pyronaridine | > 20 (30%) | > 20 (nmi) | > 20 (nmi) | 1.2/0.75 | > 20 (nmi) | > 20 (28%) |
Proguanil | > 20 (nmi) | > 20 (nmi) | > 20 (27%) | 3.5/2.2 | > 20 (24%) | > 20 (nmi) |
Primaquine | < 0.25/< 0.15 | > 20 (20%) | > 20 (34%) | > 20 (33%) | > 20 (nmi) | > 20 (31%) |
Chloroquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.1/3.8 | > 20 (nmi) | > 20 (24%) |
Chlorproguanil | > 20 (nmi) | > 20 (nmi) | > 20 (39%) | 1.4/0.87 | > 20 (41%) | > 20 (nmi) |
Azithromycin | > 20 (nmi) | > 20 (nmi) | > 20 (29%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
AQ-13 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 13/8.3 | > 20 (nmi) | > 20 (nmi) |
Desethylamodiaquine | > 18 (nmi) | > 18 (nmi) | > 18 (nmi) | 2.6/1.6 | CNDa | > 18 (nmi) |
Quinine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.0/3.7 | > 20 (nmi) | > 20 (nmi) |
Clindamycin | > 20 (nmi) | > 20 (nmi) | > 20 (32%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
KAF156 | > 20 (nmi) | 19/14 | > 20 (40%) | 1.2/0.75 | 2.7/1.6 | 2.5/1.8 |
M5717 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
OZ277 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (46%) | > 20 (26%) |
Mefloquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 16/10 | > 20 (29%) | > 20 (nmi) |
Amodiaquine | > 20 (27%) | > 20 (nmi) | > 20 (nmi) | 0.88/0.55 | > 20 (nmi) | > 20 (nmi) |
NPC1161B | 6.5/3.8 | > 20 (37%) | 9.6/5.7 | > 20 (39%) | 13.6/8.2 | > 20 (37%) |
Ferroquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.83/0.52 | > 20 (42%) | 7.3/5.2 |
Naphthoquine | > 20 (33%) | > 20 (nmi) | > 20 (nmi) | 1.1/0.68 | > 20 (38%) | > 20 (41%) |
Tafenoquine | > 20 (20%) | 14/10 | > 20 (42%) | > 20 (35%) | 3.8/2.3 | > 20 (40%) |
MMV253 | > 20 (nmi) | > 20 (nmi) | CNDa | > 20 (35%) | > 20 (37%) | CNDa |
MMV052 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Piperaquine | > 20 (nmi) | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 4.5/3.2 |
Halofantrine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.27/0.19 | > 20 (19%) | > 20 (24%) |
TDD-E209b | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (43%) | > 20 (33%) |
Lumefantrine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 2.9/1.8 | > 20 (nmi) | > 20 (nmi) |
Ionized acids at physiological pH | ||||||
Sulfadoxine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Sulfamethoxazole | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Artesunate | 20/12 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 20 (nmi) | > 20 (nmi) |
Atovaquone | > 20 (nmi) | > 20 (26%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Zwitterionic or partially zwitterionic at physiological pH | ||||||
P218 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
JPC3210 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.70/0.43 | > 20 (nmi) | > 20 (nmi) |
Neutral at physiological pH | ||||||
Dapsone | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Dihydroartemisinin | 11/6.2 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
DSM421b | > 20 (nmi) | > 20 (16%) | > 20 (nmi) | > 20 (33%) | > 20 (nmi) | CNDa |
Pyrimethamine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (36%) | > 20 (nmi) | > 20 (nmi) |
MMV048 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (16%) | > 20 (nmi) | CNDa |
Artemisone | NA | NA | NA | NA | NA | NA |
Artemether | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (37%) | > 20 (39%) |
SJ733 | > 20 (nmi) | > 20 (33%) | > 20 (38%) | 16/9.6 | > 20 (37%) | > 20 (33%) |
DSM265b | > 20 (nmi) | > 20 (25%) | > 20 (19%) | 7.1/4.4 | > 20 (34%) | CND |
KAE609 | 4.5/2.7 | 5.5/4.0 | < 0.25/< 0.15 | 5.9/3.7 | > 20 (30%) | > 20 (nmi) |
OZ439 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 5.1/3.1 | 12/8.6 |
ELQ300 | > 20 (nmi) | 7.5/5.4 | > 20 (41%) | 8.0/5.0 | > 20 (nmi) | CNDa |
Discussion
Methodology considerations
Physicochemical property trends
Case studies relating physicochemical properties to current target product profiles
Property | 8-Aminoquinolines | Peroxides | |||
---|---|---|---|---|---|
Primaquinea | Tafenoquinea | DHAb | OZ277b | OZ439b | |
Log D7.4 | 0.54 | 4.24 | 2.3 | 2.6 | > 5 |
Plasma fu | 0.26 | 0.0007 | 0.21 | 0.086 | < 0.0001 |
FaSSGF solubility (µg/mL) | > 2000 | > 2000 | 140 | > 2000 | 79 |
FaSSIF solubility (µg/mL) | > 2000 | 15.8 | 159 | > 2000 | 40.6 |
FeSSIF solubility (µg/mL) | > 2000 | 1310 | 246 | > 2000 | 526 |
Half-life (h) | 7 | 360 | 1 | 3 | > 40 |
V/F (L) | 277 | 1600 | 385 | 929 | 1570 |
CL/F (L/h) | 28 | 3.0 | 272 | 184 | 41 |
Food effect | no | yes | no | no | yes |