Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.10.092

Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue fac

Full text of DOI:10.1016/j.bmcl.2004.10.092

Bioorganic & Medicinal Chemistry Letters 15 (2005) 817–822
Design of selective phenylglycine amide tissue
factor/factor VIIa inhibitors
Katrin Groebke Zbinden,* David W. Banner, Jean Ackermann, Allan DÕArcy,
Daniel Kirchhofer, Yu-Hua Ji, Thomas B. Tschopp, Sabine Wallbaum and Lutz Weber
F. Hoffmann–La Roche Ltd, CH-4070 Basel, Switzerland
Received 9 August 2004; revised 25 October 2004; accepted 28 October 2004
Available online 23 November 2004
Abstract—Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without
enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide
tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation
cascade were designed, using the guidance of X-ray structural analysis and molecular modelling.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
factor VII circulating in the blood, leading to the initial-
ization of thrombotic processes.
Thromboembolic disorders belong to the leading causes
for morbidity and mortality in the industrialized world.
Thrombosis of either the venous or the arterial vascular
system may cause pulmonary embolism, myocardial
infarction or ischaemic stroke.1 The development of
new anticoagulant therapies represents therefore an
important medical need.
Because TF is buried in the endothelium and not ex-
posed to blood circulating in a healthy vessel, normal
haemostasis should not be affected by blockade of
F.VIIa. Indeed, proof of concept experiments from
our laboratories5 as well as other research groups6 dem-
onstrate that specific inhibition of the TF/F.VIIa com-
plex results in antithrombotic effects without
enhancing bleeding propensity. These results suggested
that F.VIIa is a very promising target for a novel antico-
agulant and stimulated substantial efforts in the phar-
maceutical industry to discover a low molecular weight
TF/F.VIIa inhibitor.7
The tissue factor/factor VIIa (TF/F.VIIa) complex is the
main trigger of thrombotic events.2 This complex is part
of the extrinsic pathway of coagulation and effects the
activation of factor X and factor IX, ultimately resulting
in the generation of thrombin. The thrombin-mediated
conversion of fibrinogen to fibrin is crucial for venous
thrombosis, whereas activation of platelets via throm-
bin-mediated cleavage of the platelet thrombin receptor
is important for arterial thrombosis.
2. Results and discussion
Screening of the Roche compound depository did not
provide a drug-like hit. Therefore lead compounds 1–4
(Table 1) were generated by a biased combinatorial
approach8 using a novel Ugi-type three-component
condensation (Scheme 1). The aminobenzamidine com-
ponent in these condensation reactions was chosen for
its potential to form a salt bridge with the Asp189 carb-
oxylate at the bottom of the S1 pocket. The resulting
phenylglycine amide compounds 1–4 are submicromolar
inhibitors of F.VIIa, but have also quite substantial
inhibitory activity against thrombin.
Tissue factor is an integral membrane protein, which is
located in the adventitia of the vessel wall, functioning
as a hemostatic envelope around blood vessels.3 Fur-
thermore, it has been described that tissue factor is
highly enriched in atherosclerotic plaques.4 Upon vessel
damage or plaque rupture, tissue factor is exposed to
*
Corresponding author. Tel.: +41 61 6888370; fax: +41 61 6889748;
e-mail: katrin.groebke_zbinden@roche.com
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.092

818
K. Groebke Zbinden et al. / Bioorg. Med. Chem. Lett. 15 (2005) 817–822
Table 1. Inhibition of TF/F.VIIa and related serine proteases by lead
compounds 1–4 and benzylamines 5–7
aniline NH and the hydroxyl group of the active site
serine (Ser 195).
R
R
R
O
O
O
A comparable binding mode is observed for compound
7 (Fig. 1B). Analogous to compound 1, the methoxy
group meta to the benzylic methylene group of com-
pound 7 is accommodated in the small S2 pocket of
F.VIIa. The S3 pocket, which is shallow and exposed
to solvent, is filled by the benzyloxy group para to the
benzylic methylene group. The sulfonamide substituent,
which is negatively charged at physiological pH is direc-
ted towards solvent. It is possibly involved in an indirect
hydrogen bond with the NH of Gly 219 via a water
molecule.
O
O
O
R'
R'
R'
O
O
S
N
H
N
H
NH
NH
NH
O
rac
H2N
H2N
NH
NH
H2N
NH
1: R = R' = Me
2: R = R' = Et
5: R = R' = Et,
7: R = Bn, R' = Me
6: R = Bn, R' = Me
3: R = Bn, R' = Me
4: R = Bn, R' = Et
From the X-ray structures of compounds 1 and 7 it be-
comes apparent that there is room to combine both the
benzylamide moiety and the sulfonamide substituent in
the same molecule. This was confirmed by preparing
compound 8 (Table 2), which has a slightly better affin-
ity for F.VIIa than compounds 3 and 7. As observed be-
fore for the benzylamine derivatives 6 and 7, the
introduction of a sulfonamide substituent ortho to Ca
of the phenylglycine moiety led to an increase in selectiv-
ity against thrombin as can be seen by comparison of
compounds 3 and 8.
Compd
Ki (lM)
Thrombin
F:VIIa
F.VIIa Thrombin F.Xa
Trypsin
1
2
3
4
5
6
7
0.35
0.04
0.22
0.13
4.2
0.46
0.57
0.043
0.048
4.5
30
19
1.7
2.0
0.21
1.1
2.0
1.3
14
5.3
4.5
39
0.2
0.4
1.1
0.3
3.7
1.0
0.38
0.27
1.4
1.20 0.58
26.0 0.40
Systematic variation of the benzylamide moiety led to
the first single digit nanomolar TF/F.VIIa inhibitor of
the phenylglycine amide class. Compound 9 has a Ki
of 4nM, but is a good thrombin inhibitor as well. Selec-
tivity could again be improved by introduction of a sub-
stituent ortho to Ca of the central phenylglycine moiety.
Both compounds 10 and 11 are characterized by low
In a first attempt to define the minimal structural
requirements for F.VIIa binding, a series of analogues
lacking the benzylamide moiety was prepared. This led
to an approximately 5–10-fold reduction of F.VIIa
affinity as exemplified by compounds 5 and 6. Affinity
was restored in compound 7 by introduction of a sulfon-
amide substituent ortho to the benzylic methylene group
as may be seen from comparison of compounds 3 and 7,
which are almost equipotent. Furthermore, the sulfon-
amide derivative 7 has a substantially improved selectiv-
ity against thrombin.
Table 2. Inhibiton of TF/F.VIIa and related serine proteases by optimized
compounds 8–11
OBn
OBn
OBn
The X-ray crystal structure of compound 1 bound to the
active site of TF/F.VIIa is shown in Figure 1A. The
amidine forms the expected salt bridge with the carboxy-
late of Asp 189 at the bottom of the S1 pocket. Addi-
tionally, a hydrogen bond is formed between the
O
O
O
R
R
H
N
H
N
H
N
α
α
α
R'
R'
R'
NH
NH
NH
O
O
O
HO
O
HO
O
rac
H2N
1 epimer
H2N
R
O
NH
H2N
NH
NH
O
R'
8: R = -SO2-Ph, R' = Bn
9: R' = Ph
10: R = -SO2-Ph, R' = Ph
11: R = -CO-CH2-Ph, R' = Ph
H
R''
N
R
H
NH2
Compd
Ki (lM)
F.VIIa Thrombin F.Xa Trypsin
2 · PTa
(lM)
Thromb:
NH
O
C
N+
O
F:VIIa
O
R'
+
a
+
8
0.16
1.7
>74
0.42
10.7
8.8
85
4
H2N
NH
H2N
NH
O
9
0.004
0.002
0.007
0.035
0.54
6.4
8.0 0.04
12.4 0.05
19.0 0.08
2 HCl
HX
10
11
270
913
12
44
1: R = R' = Me, R'' = Ph
2: R = R' = Et, R'' = Ph
a Human citrated plasma is spiked with at least six concentrations of
inhibitor. Clotting is initiated by addition of exogenous tissue factor
(Innovin). Clotting time is determined by a turbidity measurement. The
concentration of inhibitor necessary to double control clotting time is
determined by fitting the data to an exponential regression.11
3: R = Bn, R' = Me, R'' = Ph
4: R = Bn, R' = Et, R'' = Ph
Scheme 1. Preparation of lead compounds 1–4 by an Ugi-type three-
component condensation. Reagents: (a) THF/H2O 9:1.

K. Groebke Zbinden et al. / Bioorg. Med. Chem. Lett. 15 (2005) 817–822
819
Figure 1. (A) Crystals of human soluble tissue factor/factor VIIa were prepared as described9 except that proteolysis of tissue factor was not used.
˚
˚
˚
Crystals of the complex with 1 were frozen and data measured in house to 3.0A resolution. The unit cell is P212121, with a = 71.87A, b = 82.64A,
c = 123.72A. This is close to the unit cell of 1dan.pdb10 (room temperature), which was used as start model. The structure was refined to final overall
˚
crystallographic R-factors of 19.7% (working) and 25.7% (free), with values in the outer shell of 27.0% and 34.3%, respectively. The inhibitor density
is clear. The coordinates have been deposited in the Protein Data Bank as 1w2k.pdb. (B) Crystals of the complex with 7 were frozen and data
˚
˚
˚
˚
measured at the SNBL beamline at the ESRF synchrotron to 2.5A resolution. The unit cell is P212121, with a = 71.34A, b = 82.38A, c = 123.96A.
The structure was refined to final overall crystallographic R-factors of 19.9% (working) and 25.8% (free), with values in the outer shell of 23.8% and
27.9%, respectively. The inhibitor density is clear. The coordinates have been deposited in the Protein Data Bank as 1w0y.pd.
nanomolar inhibitory activity for TF/F.VIIa and a selec-
tivity against thrombin in the range of 2–3 orders of
magnitude. Unfortunately, the excellent activity of these
two compounds is not reflected by a corresponding
plasma activity in in vitro clotting assays. Twofold PT
(prothrombin time)11 prolongation, which serves as a
measure for inhibition of the coagulation cascade via
the extrinsic pathway, is only reached at concentrations
of 12lM and 44lM, respectively.
amounts of an isonitrile, a benzaldehyde and an amine
in methanol. Amines were chosen to have potential for
binding to the S1 pocket of the active site of F.VIIa. Hits
resulted eventually from a condensation between benzyl-
isonitrile, a substituted benzaldehyde and 4-aminobenz-
amidine, which was carried out in THF/H2O (Scheme 1).
The benzylamine derivatives 5–7 were prepared by
an optimized reductive amination procedure between
4-aminobenzamidine and the appropriate benzalde-
hydes (Scheme 2). The sulfonamide-substituted alde-
hyde necessary for the preparation of compound 7 was
prepared starting from 4-benzyloxy-5-methoxy-2-nitro-
benzaldehyde (Scheme 3). Protection of the aldehyde
and reduction of the nitro group gave aniline 12, which
According to the ÔRules of FiveÕ12 the high molecular
weight and the structural features of these two inhibitors
suggest poor oral bioavailability. Not surprisingly their
permeation through an artificial membrane is low. Addi-
tionally, their unfavourable pharmacokinetic profiles
(high clearance, short half life) do not allow a sufficient
plasma concentration to be achieved. Therefore the phen-
ylglycine amide TF/F.VIIa inhibitors were not consid-
ered for further development. Nevertheless, the insights
gained from X-ray structure analysis led to the discovery
of a related class of TF/F.VIIa inhibitors with potential
for oral activity. Results of these investigations will be
reported in due course.
R''
R
NH2
NH
O
R
O
O
a
+
O
R'
R'
H2N
2 HCl
NH
H2N
NH
O
H
5: R = R' = Et, R'' = H
6: R = Bn, R' = Me, R'' = H
3. Chemistry
7: R = Bn, R' = Me, R'' = Me-SO2-NH
The library of compounds, which led to the identifica-
tion of lead structures 1–4 was synthesized by a three-
component variation of the Ugi reaction,13 mixing equal
Scheme 2. Reductive amination of 4-aminobenzamidine dihydrochlo-
ride with benzaldehydes. Reagents and conditions: (a) 1equiv NaOMe,
MgSO4, MeOH; then H2, Pt/C (5%), MeOH.

820
K. Groebke Zbinden et al. / Bioorg. Med. Chem. Lett. 15 (2005) 817–822
OBn
OBn
H
OBn
OBn
O
O
O
O
O
O
a, b
c,d
OBn
H
N+ O
O
S
NH2
N+ O
O
NH2
N
H
O
H
N
+ C
N
NH
O
H
O
a
O
O
N+ O
O
+
+
O
O
12
13
rac
14
N
Scheme 3. Preparation of sulfonamide-substituted benzaldehyde 13
for the synthesis of compound 7. Reagents and conditions: (a) 2,2-
dimethyl-propanediol, p-TsOH, toluene, reflux; (b) H2, Pt/C (5%),
EtOH/dioxane 2:1; (c) MeSO2–Cl, DIPEA, DMF, CH2Cl2; (d) concd
HCl (aq), acetone.
N
b,c
OBn
OBn
O
O
O
O
O
O
was allowed to react with methanesulfonyl chloride and
subsequently deprotected to give the required aldehyde
13.
S
S
N
H
R'
d,e
N
H
R'
H
N
H
N
NH
NH
O
O
Compound 8 was prepared by starting with Lewis acid-
catalyzed condensation of 4-benzyloxy-5-methoxy-2-
nitrobenzaldehyde, benzylisonitrile and 4-aminobenzo-
nitrile to give phenylglycine amide 14 (Scheme 4).
Reduction of the nitro group and subsequent reaction
of the aniline with benzenesulfonyl chloride led to inter-
mediate 15. Finally the nitrile was converted to the ami-
dine 8 via the corresponding amidoxime.
rac
rac
H2N
NH
N
8: R' = Ph
15
Scheme 4. Preparation of sulfonamide-substituted phenylglycine
amide 8. Reagents and conditions: (a) 2equiv BF3–OEt2, allyl alcohol,
1h; (b) H2, Pd/C (10%); (c) benzenesulfonyl chloride, DIPEA, THF, rt;
(d) H2N–OH, HCl, TEA, EtOH, reflux; (e) H2, Raney nickel, EtOH/
HOAc 8:1.
The phenylglycine ester starting material 17 for the syn-
thesis of compound 9 was prepared by Lewis acid-cata-
lyzed condensation between 4-benzyloxy-3-methoxy-
benzyldehyde, 4-aminobenzonitrile and benzylisonitrile
(Scheme 5). The intermediate iminoether 16 was hydro-
lyzed in situ to the corresponding phenylglycine ester 17
by the addition of an excess of water. The synthesis was
completed by hydrolysis of the ester and coupling of
phenylglycine ester to give 18. Ester hydrolysis, chroma-
tographic separation of diastereomers and conversion of
the nitrile into the amidine via amidoxime finally led to
the desired product 9.
O
O
O
O
O
N
O
NH2
O
b
NH
N
NH
N
a
+
C
+
N+
O
O
O
H
rac
N
16
17
c, d
O
O
O
O
H
N
e, f, g
H
N
NH
NH
O
O
O
O
HO
O
epimers
9
HN
NH2
N
18
Scheme 5. Preparation of diphenylglycine derivative 9. Reagents and conditions: (a) 3equiv BF3–OEt2, MeOH, 1h, 0ꢁC; (b) in situ addition of
20equiv H2O; (c) LiOH, THF/H2O 3:1; (d) S–Phg–OMe, HCl, DIPEA, BOP, CH2Cl2; (e) LiOH, THF/H2O 3:1, separation of diastereomers by
chromatography on silica gel; (f) H2N–OH, HCl, TEA, EtOH, reflux; (g) H2, Raney nickel, EtOH/HOAc 8:1.

K. Groebke Zbinden et al. / Bioorg. Med. Chem. Lett. 15 (2005) 817–822
821
O
O
O
O
O
O
O
O
R
N+ O
O
NH2
R
N
H
NH
O
N
H
NH
H
N
C
N+
H
N
f, g, h
b, c, d, e
a
NH
N+O
O
+
+
O
O
O
O
O
HO
O
O
H
N
rac
epimers
1 epimer
HN
NH2
N
N
19
20
10: R = SO2-Ph
11: R = CO-CH2-Ph
Scheme 6. Preparation of diphenylglycine derivatives 10 and 11. Reagents and conditions: (a) 3equiv BF3–OEt2, MeOH, 1h, 0ꢁC; then in situ
addition of 20equiv H2O; (b) H2, Pt/C (5%), THF; (c) benzenesulfonylchloride or phenylacetyl chloride, DIPEA, DMF, CH2Cl2; (d) LiOH, THF/
H2O 2:1, 0ꢁC; (e) S–Phg–OMe, HCl, BOP, DIPEA, DMF; (f) LiOH, THF/H2O 2:1; (g) H2N–OH, HCl, TEA, EtOH, reflux; (h) H2, Raney nickel,
EtOH/HOAc 8:1, separation of diastereomers by chromatography on silica gel.
5. (a) Himber, J.; Refino, C. J.; Bucklen, L.; Roux, S.
Thromb. Haemost. 2001, 85, 475–481; (b) Himber, J.;
Kirchhofer, D.; Riederer, M.; Tschopp, T. B.; Steiner, B.;
Roux, S. P. Thromb. Haemost. 1997, 78, 1142–1149.
6. (a) Suleymanov, O. D.; Szalony, J. A.; Salyers, A. K.;
LaChance, R. M.; Parlow, J. J.; South, M. S.; Wood, R.
S.; Nicholson, N. S. J. Pharmacol. Exp. Ther. 2003, 306,
1115–1121; (b) Szalony, J. A.; Taite, B. B.; Girard, T. J.;
Nicholson, N. S.; LaChance, R. M. J. Thromb. Thrombol.
2002, 14, 113–121; (c) Zoldhelyi, P.; McNatt, J.; Shelat, H.
S.; Yamamoto, Y.; Chen, Z.-Q.; Willerson, J. T. Circula-
tion 2000, 101, 289–295; (d) Golino, P.; Ragni, M.; Cirillo,
P.; DÕAndrea, D.; Scognamiglio, A.; Ravera, A.; Buono,
C.; Ezban, M.; Corcione, N.; Vigorito, F.; Condorelli, M.;
Chiariello, M. Circ. Res. 1998, 82, 39–46; (e) Kelley, R. F.;
Refino, C. J.; OÕConnell, M. P.; Modi, N.; Sehl, P.; Lowe,
D.; Pater, C.; Bunting, S. Blood 1997, 89, 3219–3227; (f)
De Guzman, L.; Refino, C. J.; Steinmetz, H.; Bullens, S.;
Lipari, T.; Smyth, R.; Eaton, D.; Bunting, S. Thromb.
Haemost. 1997(Suppl. 292); (g) Harker, L. A.; Hanson, S.
R.; Wilcox, J. N.; Kelly, A. B. Haemostasis 1996,
26(Suppl. I), 76–82; (h) Pawashe, A. B.; Golino, P.;
Ambrosio, G.; Migliaccio, F.; Ragni, M.; Pascucci, I.;
Chiariello, M.; Bach, R.; Garen, A.; Konigsberg, W. K.;
Ezekowitz, M. D. Circ. Res. 1994, 74, 56–63.
The nitro-substituted phenylglycine ester 19 (Scheme 6)
was obtained using the three-component condensation
procedure described in the preceding section. Reduction
of the nitro group, derivatization of the aniline, hydrol-
ysis of the ester and coupling with phenylglycine methyl-
ester led to intermediate 20. Ester hydrolysis and
conversion of the nitrile to the amidine via the corre-
sponding amidoxime and subsequent chromatographic
separation of diastereomers led to compounds 10 and
11.
Acknowledgements
The authors wish to thank Daniel Egger, Felix Gruber,
Isabelle Guillaumat, Heidi Hoffmann Maiocchi, Frido-
lin Mehlin and Bettina Roser for their skillful technical
assistance and the staff of the Swiss-Norwegian Beam
Lines at the ESRF for professional assistance in data
collection.
References and notes
7. (a) Review: Robinson, L. A.; Saiah, E. M. K. Annu. Rep.
Med. Chem. 2002, 37, 85–94; (b) Parlow, J. J.; Kurumbail,
R. G.; Stegeman, R. A.; Stevens, M. A.; Stallings, W. C.;
South, M. S. J. Med. Chem. 2003, 46, 4696–4701; (c)
Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.;
Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.;
LaChance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare,
M.; Stegemann, R. A.; Stevens, A. M.; Stallings, W. C.;
Kurumbail, R. G.; South, M. S. J. Med. Chem. 2003, 46,
4050–4062; (d) Parlow, J. J.; Dice, T. A.; LaChance, R.
M.; Girard, T. J.; Stevens, A. M.; Stegemann, R. A.;
Stallings, W. C.; Kurumbail, R. G.; South, M. S. J. Med.
Chem. 2003, 46, 4043–4049; (e) Parlow, J. J.; Stevens, A.
M.; Stegemann, R. A.; Stallings, W. C.; Kurumbail, R. G.;
South, M. S. J. Med. Chem. 2003, 46, 4297–4312; (f)
Klingler, O.; Matter, H.; Schudok, M.; Bajaj, S. P.; Czech,
J.; Lorenz, M.; Nestler, H. P.; Schreuder, H.; Wildgoose,
P. Bioorg. Med. Chem. Lett. 2003, 13, 1463–1467; (g)
Carroll, A. R.; Pierens, G. K.; Fechner, G.; de Almeida
Leone, P.; Ngo, A.; Simpson, M.; Hyde, E.; Hooper, J. N.
1. (a) Murray, C. J.; Lopez, A. D. Lancet 1997, 349, 1269–
1276; (b) Braunwald, E.; Califf, R. M.; Cannon, C. P.;
Fox, K. A.; Fuster, V.; Gibler, W. B.; Harrington, R. A.;
King, S. B.; Kleimann, N. S.; Theroux, P.; Topol, E. J.;
Van de Werf, F.; White, H. D.; Willerson, J. T. Am. J.
Med. 2000, 108, 41–53.
2. (a) Nemerson, Y. Sem. Hematol. 1992, 29, 170–176; (b)
Edgington, T. S.; Dickinson, C. D.; Ruf, W. Thromb.
Haemost. 1997, 78, 401–405.
3. (a) Wilcox, J. N.; Smith, K. M.; Schwartz, S. M.; Gordon,
D. Proc. Natl. Acad. Sci. 1989, 86, 2839–2843; (b)
Edgington, T. S.; Mackmann, N.; Brand, K.; Ruf, W.
Thromb. Haemost. 1991, 66, 67–79.
4. (a) Annex, B. H.; Denning, S. M.; Channon, K. M.;
Sketch, M. H., Jr.; Stack, R. S.; Morrissey, J. H.; Peters,
K. G. Circulation 1995, 91, 619–622; (b) Moreno, P. R.;
Bernardi, V. H.; Lopez-Cuellar, J.; Murcia, A. M.;
Palacios, I. F.; Gold, H. K.; Mehran, R.; Sharma, S. K.;
Nemerson, Y.; Fuster, V.; Fallon, J. T. Circulation 1996,
94, 3090–3097; (c) Marmur, J. D.; Thiruvikraman, S. V.;
Fyfe, B. S.; Guha, A.; Sharma, S. K.; Ambrose, J. A.;
Fallon, J. T.; Nemerson, Y.; Taubman, M. B. Circulation
1996, 94, 1226–1232.
A.; Bostrom, S.-L.; Musil, D.; Quinn, J. R. J. Am. Chem.
¨
Soc. 2002, 124, 13340–13341; (h) Hanessian, S.; Marga-
rita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti,
L. J. Am. Chem. Soc. 2002, 124, 13342–13343; (i)
Hanessian, S.; Therrien, E.; Granberg, K.; Nilsson, I.

822
K. Groebke Zbinden et al. / Bioorg. Med. Chem. Lett. 15 (2005) 817–822
Bioorg. Med. Chem. Lett. 2002, 12, 2907–2911; (j) Young, Broger, C.; Gubernator, K. Angew. Chem., Int. Ed. Engl.
W. B.; Kolesnikov, A.; Rai, R.; Sprengeler, P. A.; Leahy,
E. M.; Shrader, W. D.; Sangalang, J.; Burgess-Henry, J.;
Spencer, J.; Elrod, K.; Cregar, L. Bioorg. Med. Chem.
Lett. 2001, 11, 2253–2256; (k) Kohrt, J. T.; Filipski, K. J.;
Rapundalo, S. T.; Cody, W. L.; Edmunds, J. J. Tetrahe-
dron Lett. 2000, 41, 6041–6044; (l) Jakobsen, P.; Horn-
eman, A. M.; Persson, E. Bioorg. Med. Chem. 2000, 8,
2803–2812; (m) Jakobsen, P.; Ritsmar Pedersen, B.;
Persson, E. Bioorg. Med. Chem. 2000, 8, 2095–2103; (n)
Roussel, P.; Bradley, M.; Kane, P.; Bailey, C.; Arnold, R.;
Cross, A. Tetrahedron 1999, 55, 6219–6230.
1995, 34, 2280–2282.
9. Kirchhofer, D.; Guha, A.; Nemerson, Y.; Konigsberg, W.
`
H.; Vilbois, F.; Chene, C.; Banner, D. W.; DÕArcy, A.
Proteins 1995, 22, 419–425.
`
10. Banner, D. W.; DÕArcy, A.; Chene, C.; Winkler, F. K.;
Guha, A.; Konigsberg, W. H.; Nemerson, Y.; Kirchhofer,
D. Nature 1996, 380, 41–46.
11. White, G. C.; Marder, V. J.; Coleman, R. W.; Hirsh, J.;
Salzman, E. Haemostasis and Thrombosis Basic Princi-
ples and Clinical Practice, 2nd ed.; Lippincott: Philadel-
phia, 1987, pp 1048–1060.
8. (a) Illgen, K.; Enderle, T.; Broger, C.; Weber, L. Chem.
Biol. 2000, 7, 433–441; (b) Weber, L. Drug Discovery
Today 1998, 3, 379–385; (c) Weber, L. Curr. Opin. Chem.
Biol. 1998, 2, 381–385; (d) Weber, L.; Wallbaum, S.;
12. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P.
J. Adv. Drug Deliv. Rev. 1997, 23, 3–25.
13. (a) Ugi, I.; Do¨mling, A.; Ho¨rl, W. Endeavour 1994, 18, 115;
(b) Ugi, I. Angew. Chem., Int. Ed. Engl. 1993, 32, 563–564.