TABLE 2

TLR7/8 inhibitor physicochemical, absorption, distribution, metabolism, and excretion, and safety properties

ParameterM5049CMPD 2
Molecular weight356.8436.6
Therm. Sol. pH 6.5 (mg/ml)>1>1
Log P2.22.3
PPB (% free) m/r/d/c/h14/15/33/35/3256/64/74/74/75
Caco-2 A > B (10−6 cm/s)2632
Caco-2 efflux ratio1.55.6
Microsomal CLint (µl/min per milligram protein) (m/r/d/c/h)<10/<10/<10/<10/<10<10/<10/<10/<10/<10
Hepatocyte CLint (µl/min per 106 cells) (m,r,d,c,h)17/11/1.6/1.5/3.1<10/6.5/<4/5.4/28
AOX cytosol CLint (µl/min per milligram protein)2.723
AOX cytosol t1/2 (h)4.30.51
P450 inhibition IC50 (µM)2D6: 3.6, others >100All > 10
P450 induction (mRNA)1A2: 2-fold@50 µM only
hERG (µM)>100>100
Ames testNegativeNegative
Kinases inhibited >50% at 1 µMaCAMKK2None
Off-target receptor activities affectedb5-HT uptakeND
  • hERG, human ether-à-go-go–related gene; 5-HT, 5-hydroxytryptamine; ND, not done; PPB, percentage protein bound; t1/2, terminal half-life; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2; Therm. Sol., thermodyanmic solubility; m, mouse; r, rat; d, dog; c, cynomolgus monkey; h, human; CLint, intrinsic.

  • a Tested in Reaction Biology 389 kinase panel.

  • b CEREP receptor profiling assay.