2144
B. Li et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2141–2144
Table 4. Inhibition of VLA-4 and a4b7 by substituted 3-pyridylacetyl
biphenylalanine derivatives (IC50, nM)
Acknowledgements
The authors are grateful to Song Zheng and Junying
Wang for formulation and mass spectral analysis, to
Marcie Donnelly and Judy Fenyk-Melody for dosing of
animals for pharmacokinetic evaluation and to Laurie
Castonguay for modeling work.
No.
R1/R2
VLA-4
0.5
a4b7
References and Notes
27
9.9
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aMixture of four isomers.
Table 5. Pharmacokinetic parameters of selected compoundsa
No.
Fb (%)
Clp (mL/kg/min)
t1/2c (h)
23
25
27
29
31
32
33
36
39
43
44
94
55
35
1
11
1
12
<1
17
6
7.5
21.5
24
2.0
1.0
1.1
NDd
0.6
0.2
>100
>100
>100
>100
>100
>100
82
0.3
ND
2.5
0.4
<1
>100
ND
aSprague–Dawley rats.
bDose: 1 mg/kg iv; 2 mg/kg po.
ct1/2=plasma half-life(0ꢀ8 h)
.
dND, not determined.
In summary, a series of potent N-(aralkyl-, arylcyclo-
alkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4
antagonists was prepared by rapid analogue methods
using solid phase chemistry. Further optimization led to
several highly potent compounds (IC50 <1 nM). Eva-
luation of rat pharmacokinetics revealed generally high
clearance.
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