2418
I. E. Kopka et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2415–2418
Table 3. Pharmacokinetic parametersa of selected compounds
Acknowledgements
The authors are grateful to Zhen Wang and Junying
Wang for formulation and mass spectral analysis and to
Marcie Donnelly, Ken Vakerich and Chris Nunes for
dosing of animals for pharmacokinetic evaluation.
No.
F
b (%)
Clp (mL/kg/min)
Vdss (L/kg)
t1/2c (h)
1
4
5
43.2
8.9
22.1
14.6
1.1
13.1
2.3
16.3
2.3
14.6
1.5
48.1
2.5
51.6
1.7
10.4
24.9
2.3
1.5
1.1
1.8
1.3
3.0
1.2
0.7
1.3
ND
1.7
ND
0.9
1.8
1.8
ND
1.6
3.2
2.4
ND
0.9
0.7
0.61
0.08
0.58
0.08
0.19
0.13
NDd
0.15
ND
0.12
1.4
0.1
0.26
1.1
0.08
0.12
0.25
0.48
0.37
21.6
13.9
19.4
12.2
42.0
8.2
55.4
19.6
38.7
7.3
25.7
1.0
45.1
2.6
21.9
1.0
18.0
1.0
13
14
15
16
17
18
25
26
27
28
28e
29
34
35
35e
36
36e
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21.7
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bDose: 1 mg/kg iv; 2 mg/kg po.
ct1/2=plasma half-life(0À8 h)
.
dND=Notdetermined.
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azetidine derivatives in Table 2. For compounds with
long plasma half-lives (13, 34, and 35), the plasma con-
centration in rats versus time curves (AUC) exhibit an
initial rapid drop in concentration followed by low
(ꢀ1 nM) but sustained circulating plasma drug levels in
vivo.
In summary, N-sulfonylated dipeptide b-biaryl-b-amino
acid derivatives are potent and specific antagonists of
VLA-4 and compliment the corresponding substituted
biphenylalaine analogues. The 2,6-dioxygenated biaryl
substitution pattern is important for optimizing
potency in both the azetidine and the proline series.
The variable oral bioavailability, clearance and poor
distribution may be directly attributed to the binding
of these peptide-like compounds to circulating plasma
proteins.
12. Results to be published in due course.