TABLE 1

Properties of novel acrylamide irreversible kinase inhibitors used to establish IVIVE in rat

NCEfupBPRCLh int, u Scaled CLhCLb int, u Scaled CLeh Scaled total CLb In vivo total CLb
µL/min/milmL/min/kgµL/min/gmL/min/kg
10.061.7549.2138354424
20.130.99452115143550
30.681.22838177211088
40.391.4252412254934
50.060.73852442244847
60.791.017358.9558976
70.030.801111462132835
80.721.217307.3366655
90.751.212247.5386365
100.811.210242.9214463
110.491.06.0133.9183135
12*0.531.3152210325453
130.401.116227.7244659
140.361.5332621366171
150.571.626297.5225156
160.781.97.61313405383
170.671.89.21521567157
180.131.6421461344838
  • Microsomal fu was ∼1 for all compounds in this chemotype.

  • * NCE 12: PF-06651600; n = 2 for fup, BPR, hepatocyte and blood CLint, u, and in vivo CLb assessments.