TABLE 1

In vitro and in silico physicochemical and biochemical properties of the 26 compounds

JNJ No.
Generic Name
mol. wt.
pKa
Log Pow
Species
fup
Fuinca
RB
In Vivo CLintb
Test System
Peff c d
Solubility
ml/min/kg 10−4 cm/s mg/ml
JNJ1 Lorcainide 407 B 9.44 4.16 Rat 0.260 1.2 624 RLMic 4.78 265, 214, 192, 2.4, 0.18 in aqueous buffer at pH 2.2, 4.2, 5.9, 7.7 and 9.5, respectively
Human 0.150 0.45 0.70 31.5 HLMic
JNJ2 Domperidone 425 B 7.89 B 2.50 3.96 Rat 0.092 1.3 178 RLMic 1.88 0.31, 1.5, 0.057, 0.006, 0.001 in aqueous buffer at pH 2.3, 4.2, 6.0, 7.2, and 8.0, respectively
Human 0.061 0.34 0.74 69.3 HLMic
JNJ3 Nebivolol 405 B 8.40 4.03 Rat 0.015 1.2 89.1 RLMic 1.86 0.046, 0.071, 0.91, 0.031, 0.12 in aqueous buffer at pH 1.9, 4.0, 5.4, 6.1, and 8.1, respectively
Human 0.020 0.12e 1.2 11.2 HLMic
JNJ4 Galantamine 287 B 8.20 1.11 Rat 0.755 1.0 20.8 RLMic 5.43 35, 39, 33, 38, 37, 41 in aqueous buffer at pH 2.0, 4.9, 5.2, 6.8, 7.5, and 7.7, respectively
Human 0.822 0.86e 1.2 2.49 HLMic
JNJ5 Alfentanil 416 B 6.50 2.21 Rat 0.164 0.69 416 RLMic
Human 0.079 0.97 0.63 190 HLMic
JNJ6 Sufentanil 386 B 8.10 4.02 Rat 0.069 0.74 250 RLMic
Human 0.075 0.87 0.74 184 HLMic
JNJ7 Ketanserin 395 B 7.50 3.30 Rat 0.012 0.65 10.0 RLMic 7.14 0.72, 1.30, 16, 15, 11, 0.050, 0.001 in aqueous buffer at pH 1.2, 2.6, 3.1, 3.5, 4.6, 5.7, and 8.0, respectively
Human 0.049 0.32 0.70 31.5 HLMic
JNJ8 Ritanserin 478 B 8.20 B 2.07 5.20 Rat 0.015 0.74 139 RLMic 12.0d 1.4, 0.063, 0.037 in aqueous buffer at pH 2.2, 4.1, and 6.1, respectively
Human 0.008 0.45 0.65 4.91 HLMic
JNJ9 Sabeluzole 415 B 7.60 B 3.40 4.63 Rat 0.016 0.84 43.0 RLMic 2.93 13, 5.8, 1.3, 3.9, 0.19, 0.01 in aqueous buffer at pH 2.7, 3.3, 4.2, 4.6, 6.0, and 6.9, respectively
Human 0.014 0.06 0.82 5.10 HLMic
JNJ10 297 B 9.47 4.03 Rat 0.141 2.0 312 RLMic 0.321 29, 11, 4.7, 2.9, 0.14, 0.061 in aqueous buffer at pH 3.4, 3.5, 4.5, 7.5, 9.14, and 12.8, respectively
Human 0.115 0.12e 1.4 10.5 HLMic
JNJ11 Lubeluzole 433 B 7.60 B 4.27 4.88 Rat 0.008 0.76 52.0 RLMic 2.79 0.013 in aqueous buffer at pH 6.9
Human 0.003 0.05e 0.58 3.90 HLMic
JNJ12 296 B 9.88 B 3.00 1.18 Rat 0.820 1.5 20.8 RLMic 0.05 20, 20, 20, 7.56, 3.09 in aqueous buffer at pH 1.8, 3.8, 4.3, 7.45, and 12.6, respectively
Human 0.867 0.85e 1.5 0.570 HLMic
JNJ13 Ridogrel 366 A 4.90 B 3.84 3.54 Rat 0.049 0.80 5.10 RLHep 4.73 0.26, 0.02, 0.65, 9.8 in aqueous buffer at pH 2.1, 5.4, 7.0, and 8.1, respectively
Human 0.033 1.0f 0.77 2.20 HLHep
JNJ14 Laniquidar 584 B 7.90 B 3.30 5.50 Rat 0.002 0.79 51.7 RLMic 4.56d 12.4, 0.58, 0.10, 0.064 in aqueous buffer at pH 2.21, 2.78, 3.62, and 7.05, respectively
Human 0.001 0.08 0.62 99.0 HLMic
JNJ15 Mazapertine 421 B 7.06 3.96 Rat 0.030 0.63 623 RLMic 5.70d 80, 43, 0.54, 0.21, 0.22 in aqueous buffer at pH 3.8, 4.7, 6.9, 8.9, and 11.5, respectively
Human 0.011 0.13e 0.52 231 HLMic
JNJ16 686 B 7.20 B 3.10 4.12 Rat 0.036 0.78 28.2 RLMic 1.85 13, 1.1, 0.75, 0.04, 0.01 in aqueous buffer at pH 2.2, 3.7, 5.7, 7.5, and 8.6, respectively
Human 0.034 0.08 0.75 20.3 HLMic
JNJ17 558 B 7.26 B 6.18 B 4.00 A 8.28 3.90 Rat 0.028 1.0 416 RLMic
Human 0.009 0.14e 1.0 231 HLMic
JNJ18 Risperidone 411 B 8.24 B 3.11 3.04 Rat 0.118 0.85 250 RLMic 5.70 40, 4.1, 1.8, 0.25, 0.064 in aqueous buffer at pH 5.4, 6.0, 6.2, 7.5, and 8.7, respectively
Human 0.100 0.34 0.67 7.96 HLMic
JNJ19 Levocabastine 420 B 9.90 A 3.20 1.75 Rat 0.465 1.1 1.25 RLHep 2.10 0.06, 0.05, 0.02, 0.02 in aqueous buffer at pH 2.0, 3.2, 6.0, and 8.0, respectively
Human 0.453 1.0f 1.2 0.33 HLHep
JNJ20 Norcisapride 313 B 9.10 B 3.00 1.51 Rat 0.650 1.5 2.43 RLMic 1.16 80, 92, 93, 74, 41 in aqueous buffer at pH 2.1, 4.8, 6.6, 7.8, and 8.0, respectively
Human
0.625
0.79e
1.6
0.88
HLMic
ml/min/kg 10 −4 cm/s mg/ml
JNJ21 481 B 7.27 3.55 Rat 0.015 1.5 35.6 RLMic 1.96 0.05 in aqueous buffer at pH 1.2, 0.003
Human 0.012 0.23 1.5 77.0 HLMic in SIF at pH 7.53
JNJ22 570 A 8.21 4.78 Rat 0.001 0.74 156 RLMic 0.751 0.002 and 100 in aqueous buffer at pH
Human 0.001 0.90 0.55 116 HLMic 6.5 and 8.7, respectively and 0.249 in
SIF at pH 7.5
JNJ23 359 B 7.00 B 3.10 3.40 Rat 0.082 0.80 208 RLMic 3.41 10.3, 3.9, 0.42, 0.035, 0.002 in aqueous
Human 0.016 0.06 0.61 10.2 HLMic buffer at pH 3.0, 4.2, 5.1, 6.0, and 8.1,
respectively
JNJ24 380 B 7.23 B 5.20 5.24 Rat 0.007 0.75 371 RLHep 2.00 20, 10.2, 2.19, 0.026 in aqueous buffer at
Human 0.006 1.0f 0.59 8.97 HLHep pH 1.4, 4.4, 5.2, and 6.0, respectively
and 0.005 SIF at pH 7.4
JNJ25 660 B 6.80 B 2.86 4.84 Rat 0.015 0.70 19.9 RLMic 4.54d 1.6, 2.43, 0.52, 0.02, 0.01 in aqueous
Human 0.016 0.05e 0.72 7.28 HLMic buffer at pH 2.1, 4.4, 5.0, 7.0, and 9.0,
respectively
JNJ26 500 B 5.95 B 3.67 4.00 Rat 0.036 1.3 24.8 RLHep 2.07 2.3, 0.18, 0.014, 0.005 in aqueous buffer
Human
0.023
1.0f
1.5
9.03
HLHep
at pH 2.3, 4.5, 5.9, and 7.5

  • A, acid; B, base; HLHep, human liver hepatocytes; HLMic, human liver microsomes; log RLHep, rat liver hepatocytes; RLMic, rat liver microsomes.

  • ↵ a Experimental values of fuinc in human microsomal protein were determined according to the method of Giuliano et al. (2005). Rat fuinc was assumed to equal human fuinc.

  • ↵ b In vivo CLint was calculated using eq. 6 as described under Materials and Methods.

  • ↵ c Permeability was measured using a Caco-2 assay and converted to Peff using the reported correlation log Peff,human = 0.6532 · log Papp,caco-2 − 0.3036 (Sun et al., 2002).

  • ↵ d In silico predicted Peff (ADMETPredictor software version 1.30.2; Simulations Plus Inc.).

  • ↵ e Predicted fuinc value in microsomes was determined according to the method of Austin et al. (2002).

  • ↵ f Hepatocyte incubation was performed in protein-free medium (fuinc = 1).