Table 3. Comparison of Key Developability Properties between Progenitor 18 and Macrocycle 19.
| progenitor 18 | macrocycle 19 | ||
|---|---|---|---|
| pIC50PI3Kδ (LE, LipE), N ≥ 3 | 6.2 (0.31, 4.6) | 7.7 (0.39, 3.4) | |
| pIC50PI3K α, β, γ, N ≥ 3 | 4.9a, 5.1, 4.6b | 5.6, 5.9, 5.8 | |
| whole blood pIC50,cN = 3 | 5.8 | 6.5 | |
| Chrom logDpH 7.4 | 1.6 | 4.3 | |
| CLND solubility (μM) | ≥406 | ≥331 | |
| AMP (nm s–1) | 140 | 530 | |
| HSA/AGP, % binding | 37/64 | 88/70 | |
| pKaH | 9.4 | 5.7 | |
| in vitro clearance (mL min–1 kg–1) | Mic | ||
| (human, | <0.40 | <0.40 | |
| minipig, | 1.63 | 0.92 | |
| rat) | 0.48 | <0.46 | |
| Hep | |||
| (human, | <0.45 | <0.45 | |
| minipig, | <0.89 | <0.89 | |
| rat) | <0.80 | <0.80 | |
a
Compound measured as <4.5 on one occasion.
b
Compound measured as <4.5 on three occasions; SD ≤ 0.32 (enzyme assays); SD ≤ 0.51 (cellular assay).
c
IFNγ inhibition in CytoStim-stimulated whole blood assay.