TABLE 1

Literature reported properties of selected inhibitors and final outcome of the experiment

DSBSFBPPZECDCCMLPB
Known parameters from literature and databaseMolecular weight (g/mol)488.01464.83383.37563.65368.38581.06
Predicted solubility (µM) (DrugBank database)26.233.681291.184.9915.6138.38
Predicted logP (DrugBank database)2.774.122.116.813.625.18
Reported IC50 (µM)3.1a5.5b0.31c1.6d0.025e
Clinical informationDose100 mg once dailyf400 mg twice a day40 mg Once dailyg400 mg twice a dayg2 g Once dailyg1250 mg dailyg
Cmax (µM)0.46f6.45h6.5g0.327g4.2g
Igut/IC50111067g9200g14,000g21,0000g
Cmax/IC502.081.2g1.1g170g
Possible DDINoYesYesYesYesYes
PK information from miceDose (mg/kg)10404010030090
Cmax (µM)∼0.7i21a0.78j∼0.06k∼10l
Tmax (h)0.25–21m81.50.5–1
t1/2 (h)20123
Prediction of possible outcome in mouse based on selected dose and observed IC50Observed IC50 (µM)22.762.1811.190.212.520.04
Cmax/IC500.039.633.710.02250
Oral dose for mice study (mg/kg)10404010030090
Cgut (µM)63926893260554425,4494840
Cgut/IC5028123329126,40010,098121,000
Cgut_soluble/IC501.21.7115.423.76.2959.5
Expected oral DDIYesYesYesYesYesYes
In vivo serum concentration resultAUCSerum 0–6 h (µM/h)0.11 ± 0.0020.13 ± 0.020.18 ± 0.010.46 ± 0.080.70 ± 0.11.24 ± 0.09
Fold change over control1.241.452.025.177.7913.78
Observed DDI?NoNoYesYesYesYes
Live animal fluorescence resultAUCFL 0–6 h5.82 ± 1.276.98 ± 1.157.30 ± 0.7410.55 ± 2.1211.2 ± 1.7511.66 ± 1.54
Fold change over control1.21.441.502.172.312.4
Observed DDI?NoNoYesYesYesYes
  • t1/2, half-life; Tmax, time for maximal plasma concentration; Cgut_soluble is soluble fraction of the drug in the gut, assumed to be equal to predicted solubility.

  • a Hu et al. (2009).

  • b Suzuki et al. (2009).

  • c Ahmed-Belkacem et al. (2005).

  • d Kusuhara et al. (2012).

  • e Polli et al. (2008).

  • f Di Gion et al. (2011).

  • g Lee et al. (2015).

  • h Strumberg et al. (2007).

  • i Kamath et al. (2008).

  • j Sane et al. (2012).

  • k Zhongfa et al. (2012).

  • l Hudachek and Gustafson (2013).

  • m Lagas et al. (2010).