TABLE 5.
In vitro biochemical and in vivo properties of imidazopyrimidazine inhibitors of PfCDPK1
| Compound | Parasite growth inhibition EC50 (nM)a | ΔTm PfCDPK1 (K) | IC50 (nM)b |
% reduction in parasitemia in vivo (po)c | PAMPA Papp (nm/s)d | mlogDd | |||
|---|---|---|---|---|---|---|---|---|---|
| WT PfCDPK1 | PfCDPK1 T145Q | PbCDPK1 | PvCDPK1 | ||||||
| 1 | 439 (216) | 16 | <10 | 4,610 (780) | 22 (4) | <10 | 46 (4) | 81 | 3.4 |
| 2 | 13 (1) | 28 | <10 | 2,350 (150) | <10 | <10 | 4 (14) | 4 | 0.2 |
| 3 | 407 (32) | 21 | <10 | 1,303 (494) | 15 (4) | <10 | 44 (16) | 171 | 3.2 |
| 4 | 297 (154) | 22 | 11 (4) | 2,788 (704) | 43 (13) | <10 | 46 (1) | 92 | 2.8 |
| 5 | 294 (167) | 20 | 30 (13) | 1,482 (518) | 142 (44) | 37 (21) | 34 (20) | 81 | 3.3 |
| 6 | 77 (32) | 22 | <10 | 2,201 (424) | <10 | <10 | 51 (3) | 48 | 3.7 |
| 7 | 75 (34) | 23 | <10 | 344 (64) | <10 | <10 | 18 (22) | 18 | 2.2 |
a
Mean EC50 values determined by FACS (n = 3) (standard deviations [SD] shown in parentheses).
b
Mean IC50 values determined using Rh-ParM to detect ADP in the absence of MTIP (n = 3) (SD shown in parentheses).
c
Mean reduction in parasitemia in mice (groups of three mice) given dosage of 50 mg/kg of body weight administered per os (po) (SD in parentheses) (data derived from reference 26).
d
Parallel artificial membrane permeability assay (PAMPA) apparent permeability (Papp) (in nm/s) and measured distribution coefficient (mlogD) are in vitro ADMET properties (data derived from reference 26).