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. Author manuscript; available in PMC: 2017 Jul 18.
Published in final edited form as: Nature. 2016 Sep 7;538(7625):344–349. doi: 10.1038/nature19804

Extended Data Table 3.

In vitro and in vivo pharmacokinetic properties of the bicyclic azetidine series

BRD3444* BRD1095* BRD7929* BRD7929† BRD3316*
Pf, Dd2 EC50 (nM) 9 10 9 23
PBS solubility (µM) < 1 25 15 91
Mouse Plasma protein binding (%) 99.9 99.3 99.9
Mouse Clint (µL/min/mg) 248 < 20 21 38
Human Clint (µL/min/mg) 142 < 20 31 34
HepG2 CC50 (µM) > 50 15.6 9 > 50
hERG IC50 (µM) 5.2 5.1 2.1 > 10
Route (mg/kg) IV (3) PO (10) IV (3) PO (10) IV (2.5) IV (2.5)‡ PO (10) PO (3) PO (9) IV (3.2) PO (13)
    Cmax (µM) 0.6 0.6 0.54 0.21 0.6 6.8
    Tmax (hr) 0.5 4 8 12 12 1
    T1/2 (hr) 3.7 3.2 28.8 N.C 32 2.3 2.4
    AUC0-t (µM*hr) 1.2 4 7 11.7 3.5 9# 11 6.4 19.7 13..2 33.5
    AUC0-inf (µM*hr) 1.4 4 14.9 11.2 7.2 22.6 13.2 33.5
    MRT0-inf (hr) 2.8 39.2 40.5 45 35.4 37.8 3.3 3.9
    Vss (L/kg) 12 16 24 19 1.4
    F (%) 86 50 79.5§ 63
    CL (mL/min/kg) 72 6.7 9.9 7.1 7.1

BRD3444 and BRD1095 were formulated in 70% PEG400 and 30% aqueous glucose (5% in H2O) for intravenous and oral dosing and pharmacokinetics were determined in CD-1 mice as described in Methods. Pharmacokinetic studies of BRD3444 and BRD1095 were performed by ChemPartner Co., Ltd and were estimated by a non-compartmental model using WinNonlin 6.2. BRD7929 and BRD3316 were formulated in 10% ethanol, 4% Tween, 86% saline for both intravenous and oral dosing. Pharmacokinetics in P. falciparum 3D7HLH/BRD-infected NSG mice was determined on dried blood spot samples from infected NSG mice using standard methods. Pharmacokinetics parameters for BRD7929 and BRD3316 were estimated by a non-compartmental model using proprietary Eisai software. Clint, intrinsic clearance; CL, clearance; MRT, mean resistance time; N.C, not calculated owing to insufficient data; Vss, steady-state volume of distribution.

*

Pharmacokinetic in CD-1 mice.

†

Pharmacokinetic in P. falciparum 3D7HLH/BRD-infected NSG mice.

‡

Intravenously determined in a separate assay over 72 h to determine half-life.

t = 24 h.

#

t = 72 h.

§

Per cent value based on initial intravenous study at 24 h.