W. B. Young et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2253–2256
2255
lengths of both 6 and 11, while the length of 12 may not
be optimal. The anionic charge on compound 13 is
likely extended out far enough to interact with Lys60A
and this may explain its improved potency.
levels while 14 is slightly more effective. Compound 15
was the least effective. In-house studies have indicated
that by effectively decreasing the lipophilicity of such
compounds (i.e., increasing water solubility/decreasing
plasma protein binding) a marked improvement in the
anticoagulant effect has been shown. It is also realized
that the selectivity profile of the inhibitors plays a role
in the overall anticoagulant effect.
The in vitro anticoagulant effect (prothrombin times,
PTs) of several lead analogues is listed in Table 2.
Compounds 6, 11–12 double the PT at low micromolar
The synthesis of 6, starting from commercially available
methyl 4-hydroxyphenylacetate (16), is illustrated in
Scheme 1. Formylation of 16 with MgCl2 and paraform-
aldehyde, bromination with NBS, and subsequent
treatment with methoxyethoxymethyl chloride afforded
17. A Suzuki coupling of 17 with the commercially
available boronic acid 18 followed by treatment with
dimethyl-1-diazo-2-oxopropylphosphonate19 afforded
alkyne 19. A palladium(0) catalyzed coupling of 19 with
the aryl iodo moiety 20 then gave 21. Removal of the
protecting groups and transformation of the nitrile into
an amidine via standard Pinner/aminolysis conditions
afforded 6. All other analogues described were syn-
thesized in an analogous manner to 6, although the
requisite boronic acids or a modified starting phenol
moiety was utilized.12
Table 2. C50 modifications
0
Ki (nM)
FVIIa/TF
Compd
R
Selectivity ratio
2xPT
(mM)
fXa fIIa Plasmin Trypsin uPa
11
6
5
3
42 420
75
90
6
70
160
37
63
5
44 4.1
64 1.7
20 960
12
13
14
15
27
3
2
5
59
6
2.2
The optimization of a nonselective serine protease
screening lead to a 3 nM factor VIIa/TF inhibitor,
which possesses improved selectivity versus relevant
anti-targets, is described. Pharmacokinetics, in vivo
animal efficacy, and non-amidino P1 analogue develop-
ment will be the subject of a future publication.
870
33
3
21 na
50
50
0.5 40
0.5 140
1
0.73
20
40
15 16
Acknowledgements
The authors wish to thank Michael Venuti and Jochen
Knolle for helpful scientific discussions, Liling Fang for
analytical support and Barbara Nielsen for aid in
preparing this manuscript.
References and Notes
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Scheme 1. Palladium(0) catalyzed route to 6. Reagents: (a) MgCl2,
(CH2O)n, MeCN; (b) NBS, DMF; (c) MemCl, Hunig’s base; (d) 18,
Pd(PPh3)4 1 M Na2CO3, toluene, reflux; (e) dimethyl-1-diazo-2-oxo-
propylphosphonate, K2CO3, MeOH; (f) 20, Pd(PPh3)2Cl2, CuI, NEt3,
MeCN, 80 ꢁC; (g) NaOH, THF; (h) EtOH, HCl (anhyd); (i) NH3,
EtOH; (j) 1 N HCl, reflux.