TABLE 2

In vitro ADME properties of SB939

Valuea
LogDpH
    LogD2.06−3.59 ± 0.01
    LogD3.35−2.21 ± 0.10
    LogD5.430.28 ± 0.05
    LogD6.771.65 ± 0.04
    LogD7.402.07 ± 0.04
    LogD8.942.40 ± 0.03
In vitro PPBb
    Mouse93.9 ± 1.5
    Rat93.0 ± 4.4
    Dog83.5 ± 1.8
    Human91.8 ± 0.3
    B/Phuman ratio0.97 ± 0.03
Caco-2 bidirectional permeabilityc
    A→B7.0
    B→A19.4
    Efflux ratio (Papp,B-A/Papp,A-B)2.8
In vitro metabolic stabilityd
    MLM30.0
    RLM60.0
    DLM6.0
    HLM13.0
In vitro metabolic stability (rhP450)e
    CYP1A20.89
    CYP2C9Stablef
    CYP2C19Stablef
    CYP2D6Stablef
    CYP3A40.18
In vitro P450 inhibitiong
    CYP1A2>25
    CYP2C9>25
    CYP2C195.8 ± 5.9
    CYP2D6>25
    CYP3A4>25
  • rhP450, recombinant P450.

  • a Mean ± S.D.

  • b Data are shown as mean ± S.D. and are percentage bound.

  • c Data are shown as mean and Papp (×10−6 cm/s).

  • d Data are shown as mean and Clint (μl · min−1 · mg−1).

  • e Data are shown as mean and Clint (μl · min−1 · pmol CYP450−1).

  • f More than 80% of parent present at the end of incubation.

  • g Data are shown as mean ± S.D. and IC50 (micromolar).