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Vol. 292, Issue 1, 351-357, January 2000
Cardiovascular Diseases Research (P.C.W., E.J.C., C.A.W., R.M.K.) and Chemical and Physical Sciences (M.L.Q., R.R.W.), DuPont Pharmaceuticals Company, Wilmington, Delaware
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as KI and IC50, respectively. A highly significant correlation was found between KI and IC50 (r = 0.93, P < .0001). The antithrombotic effects of SF303 [mol. wt. 536; KI: fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; KI: fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [KI(fXa) = 0.5 nM], DX-9065a [KI(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID50 values for preventing arteriovenous shunt-induced thrombosis were 0.6 µmol/kg/h for SF303, 0.035 µmol/kg/h for SK549, 0.01 µmol/kg/h for recombinant tick anticoagulant peptide, 0.4 µmol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC50 of 0.062 µM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 ± 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
clinical usefulness of anticoagulants such as warfarin (Coumadin) and
the successful development of low molecular weight heparins (LMWHs) for
the treatment and prevention of thromboembolic diseases have generated
a great interest in searching for new anticoagulants (Turpie, 1998
).
However, warfarin is an indirect inhibitor of blood coagulation and
takes several days to reach effective anticoagulant levels. LMWH
requires a physiological cofactor, antithrombin III, to inactivate
factor Xa (fXa). Therefore, the current drug discovery research focuses
on designing small molecule inhibitors that directly act on coagulation
factors such as thrombin and fXa.
The direct thrombin inhibitors have shown good antithrombotic efficacy
in animal thrombosis models. However, it is not certain whether the
antithrombotic effects of these inhibitors can be achieved without
bleeding complications in humans (Turpie, 1998). The alternative target
of new anticoagulants is inhibition of the earlier sites of the
coagulation cascade such as fXa. fXa plays a major role in blood
coagulation because of its central position at the convergent point of
the intrinsic and extrinsic pathways of coagulation. It is believed
that inhibition of fXa may reduce the production of thrombin by either
the extrinsic or intrinsic pathways without interfering with a basal
level of thrombin activity necessary for normal hemostasis
(Harker et al., 1997).
Both peptide and nonpeptide fXa inhibitors are currently available
(Kaiser, 1998; Hauptmann and Stürzebecher, 1999). Antistasin and
tick anticoagulant peptide, examples of peptide fXa inhibitors, are
isolated from blood-sucking animals (Kaiser, 1998). DX-9065a and
YM-60828, examples of low molecular weight nonpeptide fXa inhibitors,
are chemically synthesized (Hara et al., 1994; Taniuchi et al., 1998).
The antithrombotic effects of these peptide and nonpeptide fXa
inhibitors have been well demonstrated in various experimental models
of arterial and venous thrombosis (Kaiser, 1998; Hauptmann and
Stürzebecher, 1999).
Because GluGlyArg (EGR), the substrate sequence of prothrombin for fXa,
is similar to the sequence of ArgGlyAsp (RGD) of the platelet
glycoprotein (GP) IIb/IIIa receptor, we reasoned that compounds
designed originally as GP IIb/IIIa receptor antagonists might have
affinity for fXa (Quan et al., 1997). Accordingly, we tested our
library of GP IIb/IIIa receptor antagonists and identified several weak
benzamidine isoxazoline compounds with KI values of less than 50 µM for fXa
(Fig. 1; Quan et al., 1997). Based on
these prototype molecules, we initiated structure-activity studies that
led to the synthesis of a potent bisbenzamide fXa inhibitor with a
KI of 94 nM (Quan et al., 1997).
Because of poor pharmacokinetic profiles of bisbenzamide compounds, we
focused on designing monobasic fXa inhibitors (Quan et al., 1999a,b). The replacement of the benzamidine group with a biphenyl group resulted in the synthesis of SF303, which has a
KI of 6.3 nM for fXa (Quan et al.,
1999a,b). Subsequently, we replaced the ester side chain of SF303 with
a tetrazole side chain and made SK549, which represented our first
breakthrough into orally active fXa inhibitors (Quan et al., 1999a,b).
In this report, a series of benzamidine isoxazoline derivatives of fXa
inhibitors was evaluated in vitro for their inhibitory effects on human
fXa activity and on antithrombotic activities in a rabbit model of
arteriovenous shunt thrombosis (AVST). Furthermore, SF303
((±)-5-isoxazoleacetic acid,
3-[3-(aminoiminomethyl)phenyl]-5-[[[2'-(aminosulfonyl)-[1,1'-biphenyl]-4-yl]-amino]carbonyl]-4,5-methyl ester-trifluoroacetic acid salt) and SK549
((
)-5-isoxazolecarboxamide, 3-[3-(aminoiminomethyl)phenyl]-N-5-[2'-(aminosulfonyl)-[1,1'-biphenyl]-4-yl]-4,5-dihydro-5(1H-tetrazol-1-ylmethyl)-trifluoroacetic acid salt) were selected for additional characterization.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Reagents.
The following drugs and chemicals were used in
this study: chromogenic substrates, S-2765, S-2366,
S-2222, S-2251, and S-2765 (Chromogenix AB products
distributed by DiaPharma Group, Inc., West Chester, OH);
Spectrozyme-tPA (tissue plasminogen activator; American Diagnostica
Inc., Greenwich, CT); human 
-thrombin, trypsin, and fXa (Enzyme
Research Laboratories, Inc., South Bend, IN); human tissue plasminogen
activator (tPA) and plasmin (American Diagnostica); human 
-thrombin
(ICN Biomedicals, Inc., Costa Mesa, CA); activated partial
thromboplastin time (APTT) reagent, ADP, and thromboplastin with
calcium (Sigma Chemical Co., St. Louis, MO); heparin (Upjohn,
Kalamazoo, MI); and dalteparin (fragmin; Pharmacia AB, Stockholm,
Sweden). Nonpeptide fXa inhibitors listed in Fig.
2 and DX-9065a were synthesized at DuPont
Pharmaceuticals Co. (Wilmington, DE). Purified recombinant tick
anticoagulant peptide (rTAP) was prepared from culture medium of
Saccharomyces cerevisiae as described by
Neeper et al. (1990) with modifications.
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Inhibitory Effects on Serine Proteases.
The affinity of test
compounds for human fXa, thrombin, trypsin, tPA, and plasmin was
determined by using the chromogenic substrates S-2765,
S-2366, S-2222, Spectrozyme-tPA, and S-2251, respectively, as reported previously by Kettner et al. (1990). Assays
were performed in a Hewlett-Packard (Palo Alto, CA) model 8452A
spectrophotometer with a temperature-controlled multicell transport
system. The hydrolysis rates of chromogenic substrates were assayed by
continuously measuring absorbance at 405 nm at 25°C. The
KI values were determined by the
Lineweaver-Burk method.
Antithrombotic Studies.
Experiments, using a modification of
the methods of Wong et al. (1996), were conducted on male New Zealand
White rabbits that were anesthetized with ketamine (50 mg/kg i.m.) and
xylazine (10 mg/kg i.m.). These anesthetics were supplemented as
needed. The femoral artery, jugular vein, and femoral vein were
isolated and catheterized. A saline-filled arteriovenous (AV) shunt
device was connected between the femoral arterial and femoral venous cannulas. The AV shunt device consisted of an outer piece of Tygon tubing (length, 8 cm; i.d., 7.9 mm) and an inner piece of tubing (length, 2.5 cm; i.d., 4.8 mm). The AV shunt also contained an 8-cm
length of 2-0 silk thread (Ethicon, Somerville, NJ). Blood flowed from
the femoral artery via the AV shunt into the femoral vein. The exposure
of flowing blood to a silk thread induced the formation of a
significant thrombus. After 40 min, the shunt was disconnected and the
silk thread, which was covered with thrombus, was weighed.
Clotting Assay.
Arterial blood samples were collected using
one-tenth volume of 0.109 M sodium citrate as anticoagulant and then
centrifuged. APTT and PT were measured on a fibrometer (BBL
Fibrosystem, Becton Dickinson, Cockeysville, MD) (Kettner et al.,
1990). APTT was measured by incubating 100 µl of plasma with 100 µl
of APTT reagent for 3 min, followed by addition of 100 µl 25 mM
CaCl2. PT was measured by incubating 100 µl of
plasma for 2 min at 37°C, followed by addition of 200 µl of
prewarmed thromboplastin with calcium. Data points were the means of
duplicate measurements and were expressed as a ratio of treated samples
versus baseline control.
Platelet Aggregation.
Platelet-rich plasma was prepared by
centrifugation of fresh citrated blood collected from rabbits. Platelet
aggregation was measured with a platelet aggregometer (model PAP-4D,
BioData, Horsham, PA). Platelet-rich plasma (200 µl) was mixed with
20 µl of either saline or 1 µM SK549 in saline and incubated for 3 min at 37°C. Percentages of platelet aggregation were determined 4 min after the addition of 20 µl of the agonist (10 µM ADP and 35 nM
-thrombin, final concentrations).
Statistical Analysis.
The statistical analyses that we used
were correlation, linear regression, analysis of variance, and
Duncan's new multiple-range test (Cody and Smith, 1991). A value of
P < .05 was considered statistically significant. All
data are means ± S.E.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In Vitro Characterization of SF303 and SK549
SF303 (mol. wt. 536) and SK549 (mol. wt. 546) were evaluated for inhibitory potency against several human proteases. Inhibitory constants (KI) for SF303 (fXa, 6.3 nM; thrombin, 3100 nM; trypsin, 110 nM; tPA >20000 nM; plasmin, 2500 nM) and SK549 (fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tPA >33000 nM; plasmin, 890 nM) show them to be potent and selective small molecule inhibitors of fXa. rTAP and DX-9065a were included for comparison. rTAP inhibited human fXa with a KI value of 0.5 nM. DX-9065a was less potent than SF303 and SK549 and inhibited human fXa with a KI value of 30 nM.
AV Shunt Model in Rabbits
Antithrombotic Effects of Heparin, rTAP, DX-9065a, and
Dalteparin.
Allowing blood to flow through the AV shunt for 40 min
led to the formation of a thrombus weighing approximately 350 mg. In this model, heparin, rTAP, DX-9065a, and dalteparin, given as an i.v.
infusion 1 h before blood was circulated in the shunt, inhibited
formation of the thrombus in a dose-dependent fashion with
ID50 values of 21 U/kg/h, 0.01 µmol/kg/h, 0.4 µmol/kg/h, and 23 U/kg/h, respectively (Figs.
3 and 4).
Dalteparin, given s.c. at 100, 200, and 400 U/kg, caused a
dose-dependent antithrombotic effect; the maximum antithrombotic
effects for these doses occurred at 200 min postdose (data not shown).
The ID50 for s.c. dalteparin was 182 U/kg (Fig.
4).
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Relationship Between KI(fXa) and In Vivo
Potency IC50.
A series of benzamidine isoxazoline
derivatives of fXa inhibitors was evaluated against purified human fXa
for their inhibitory effects on fXa activity and in a rabbit model of
AVST for their antithrombotic activities, expressed as
KI and IC50,
respectively (Fig. 2). Although there was a significant correlation
between KI and
ID50 (r = 0.85, P < .0003), we found a better and highly significant correlation between
KI and IC50
(r = 0.93, P < .0001) as shown in Fig.
5.
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Antithrombotic Effects of SF303 and Its Enantiomers.
As shown
in Fig. 6, SF303 produced a
dose-dependent antithrombotic effect with an ID50
of 0.6 µmol/kg/h. SG007, the positive enantiomer of SF303, inhibited
human fXa with a KI of 7 nM and an
ID50 of 2 µmol/kg/h i.v. (Fig. 6). SG008, the
negative enantiomer of SF303, had a
KI(fXa) of 4 nM and an
ID50 of 0.2 µmol/kg/h i.v. (Fig. 6).
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Effects on APTT.
Effects of SF303 on APTT were compared with
heparin, rTAP, and DX-9065a (Fig. 7).
Heparin, given i.v. at 64 U/kg/h, significantly increased APTT
(P < .05). rTAP, given i.v. at 0.01 to 0.36 mg/kg/h, and SF303, given i.v. at 0.04 to 1 mg/kg/h, did not alter APTT levels
significantly. DX-9065a, given i.v. at 0.2 and 1 mg/kg/h, significantly
prolonged APTT (P < .05).
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Antithrombotic Effects of SK549.
As show in Fig.
8, SK549 produced a dose-dependent
antithrombotic effect with an ID50 of 0.035 µmol/kg/h. Effects of the saline vehicle and SK549 on PT were
evaluated in a separate group of experiments. Compared with the vehicle
(n = 3), SK549 at 0.008 (n = 4), 0.04 (n = 4), 0.2 (n = 4), and 1 (n = 4) mg/kg/h i.v. did not alter PT (1 ± 0.06, 1.08 ± 0.06, 1.08 ± 0.05, 1.1 ± 0.06, and 1.18 ± 0.1 for the vehicle; SK549 at 0.008, 0.04, 0.2, and 1 mg/kg/h,
respectively). In vitro effects of SK549 on platelet aggregation were
also studied. At 1 µM, SK549 did not alter the platelet aggregation
induced by either ADP or -thrombin [ADP, 48 ± 3% for the
vehicle (n = 6) and 50 ± 2% for SK549
(n = 4); -thrombin, 56 ± 2% for the vehicle
(n = 6) and 49 ± 1% for SK549 (n = 4)].
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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With the emphasis on structure-based design, a series of
potent benzamidine isoxazoline fXa inhibitors was synthesized (Quan et
al., 1999a,b). Unlike DX-9065a and YM-60828 (Hara et al., 1994; Taniuchi et al., 1998), which are dibasic compounds, these benzamidine isoxazoline fXa inhibitors are monobasic. Our data suggest that the
structural requirement for potent fXa inhibitors does not necessarily
require two basic moieties. Moreover, replacing the strongly basic
para-benzamidine group of the bisbenzamidine fXa inhibitor
(Fig. 1) with a substituted biphenyl moiety improves inhibitory potency
against fXa. For instance, the monobasic fXa inhibitor SK549 is very
potent with subnanomolar affinity for fXa and is 58 and 2.5 times more
potent in terms of KI than DX-9065a (KI = 30 nM) and YM-60828
(KI = 1.3 nM, reported by Taniuchi et al., 1998), respectively. Our results also suggest that monobasic isoxazoline fXa inhibitors still retain selectivity. When compared with
the other serine proteases, SF303 and SK549 were at least 397 to 1712 times more potent in inhibiting fXa than thrombin, tPA, and plasmin,
and 17 and 87 times more potent than blocking trypsin, respectively.
To examine the efficacies of these benzamidine isoxazoline fXa
inhibitors, we evaluated these agents in a rabbit model of AVST. We
selected the rabbit as our animal model because rabbit and human fXa
have similar binding affinity to enzyme substrate and small molecule
inhibitors of fXa (Hara et al., 1995; RMK, unpublished observation). In
contrast, rat and dog fXa are much less sensitive to small molecule
inhibitors of fXa (Hara et al., 1995; Taniuchi et al., 1998; R.M.K.,
unpublished observation). Because rTAP and nonpeptide fXa inhibitors
such as DX-9065a and YM-60828 have been well characterized in the AVST
model (Hara et al., 1994; Wong et al., 1996; Sato et al., 1998),
we evaluated our isoxazoline fXa inhibitors in this model. The AVST
model has been characterized as a `mixed' thrombosis model. In this
model, the thrombosis is probably initiated by platelet adherence to the silk thread anchored in the shunt and both the activation of
platelets and the coagulation cascade contribute to the thrombus formation (Peters et al., 1991).
This study shows that heparin and the LMWH dalteparin are effective in
inhibiting thrombus formation in the rabbit AVST model. When given
s.c., dalteparin inhibited the thrombus formation dose dependently in
the AVST model with an ID50 of 182 U/kg. Because the clinical effective dose of dalteparin for the treatment of deep
vein thrombosis is 100 to 200 U/kg s.c. (Dunn and Sorkin, 1996), our
results suggest that the degree of severity of thrombosis in the AVST
model is similar to that in deep vein thrombosis. In this model, rTAP
is a very potent antithrombotic agent with an
ID50 of 0.01 µmol/kg/h. A similar efficacy of
rTAP in inhibiting AV shunt-induced thrombosis has also been reported
in rats (Wong et al., 1996). We also confirmed that DX-9065a is
an effective antithrombotic agent in the rabbit thrombosis model with
an ID50 of 0.4 µmol/kg/h. The observed potency
of DX-9065a in this study is consistent with the previously reported
potency by Nagahara et al. (1995). Because rTAP and DX-9065a are potent
and selective fXa inhibitors, the observed antithrombotic efficacies of
both agents support the inhibition of fXa as an attractive
anticoagulant target in thrombotic diseases.
To substantiate that the antithrombotic effect of benzamidine isoxazoline fXa inhibitors is due to the inhibition of fXa, the correlation between the inhibitory constants for the fXa, KI, and the in vivo antithrombotic potencies, IC50, of a series of benzamidine isoxazoline fXa inhibitors was determined. It should be noted that plasma concentrations of all these fXa inhibitors except SK549 were determined by the anti-fXa assay. This functional assay did not take the contribution of potentially active metabolites into account. However, our study shows an excellent correlation between KI and IC50, suggesting that the contribution of potentially active metabolites of these fXa inhibitors to the readout of the anti-fXa assay may be minimal. Furthermore, the excellent correlation supports that the inhibition of fXa is the primary mechanism of the antithrombotic effects of nonpeptide fXa inhibitors. It is interesting that the IC50 of this series of fXa inhibitors averaged approximately 150-fold greater than the KI. Reasons for this difference between KI and IC50 are not clear, but may be due to differences between in vitro and in vivo experimental conditions, e.g., protein binding and inhibition kinetics.
To illustrate the characteristics of benzamidine isoxazoline derivatives of fXa inhibitors, SF303 and SK549 were selected for additional study. SF303 is a selective and competitive fXa inhibitor with a KI of 6.3 nM. It is also a potent antithrombotic agent in the AVST rabbits with an ID50 of 0.6 µmol/kg/h. Because SF303 is a racemic mixture, we studied its enantiomers in the anti-fXa assay and in the AVST rabbits. Our results indicate that the negative enantiomer of SF303, SG008, is more potent than the positive enantiomer, SG007, both in terms of inhibitory constants for fXa (KI) and in vivo antithrombotic potency (ID50). These results suggest that the binding of SF303 to the active site of fXa is stereospecific and depends on the configuration of SF303 presenting its chiral center to the active site.
APTT is used universally to monitor the therapeutic level of
heparin-induced anticoagulation (Kher et al., 1997). The dose of
heparin that doubles the APTT is often taken as a measure of adequate
heparin administration. In this study, although heparin, at its
antithrombotic ID50, only minimally prolonged
APTT, it produced a greater than 5-fold increase in APTT at its maximum antithrombotic dose. By contrast, maximum inhibition of thrombus formation was achieved with selective fXa inhibitors, including rTAP,
DX-9065a, and SF303, that only minimally prolonged APTT. In addition,
the antithrombotic efficacy of SK549 was not correlated with any change
in PT. Other studies have also shown that fXa inhibitors such as rTAP,
DX-9065a, and YM60828 produced antithrombotic efficacy without the
prolongation of APTT seen in animal experiments (Wong et al., 1996;
Hauptmann and Stürzebecher, 1999). It is still not known whether
a lower level of anticoagulation induced by fXa inhibitors may account
for the reduced bleeding time observed in animals (Harker et al., 1997;
Hauptmann and Stürzebecher, 1999).
Our study shows, for the first time in the rabbit AVST model, that
monobasic isoxazoline compounds, such as SF303, SK549, and their
analogs, are potent antithrombotic agents. SK549 is as potent as rTAP
in inhibiting fXa activity in vitro
(KI for both compounds is
approximately 0.5 nM). In the AVST rabbits, SK549 given i.v. was only
3.5 times less potent than rTAP given i.v., which may be related to
enhanced inhibitory potency of rTAP in the prothrombinase complex (for
review see Kaiser, 1998). However, rTAP lacks oral activity because of
its peptidic nature. In this regard, SK549 is better than rTAP. When
given intraduodenally, SK549 exerted a long-acting antithrombotic
effect in the rabbit AV shunt model of thrombosis, suggesting that
SK549 may be active after oral administration. It should be noted that
the antithrombotic effect of SK549 may not be due to the inhibition of
platelet aggregation because 1 µM SK549 (17-fold greater than its
IC50 of 0.064 µM) did not affect platelet
aggregation in vitro.
In summary, our study shows that SF303 and SK549 are effective antithrombotic agents in a model of thrombosis in rabbits. Unlike heparin, the antithrombotic actions of fXa inhibitors at the maximal doses studied were associated with a minimum degree of anticoagulation. Because our study shows an excellent correlation between KI and IC50 of a series of benzamidine isoxazoline fXa inhibitors, it suggests that the inhibition of fXa is the primary mechanism of the antithrombotic effects of these inhibitors. Because most of the reported small molecule fXa inhibitors, such as DX-9065a and YM-60828, are dibasic compounds whose therapeutic applications may be limited by poor pharmacokinetics, we believe this new series of monobasic isoxazoline fXa inhibitors may eventually lead to compounds with better pharmacokinetics. Thus, this series of small nonpeptide inhibitors represents a new class of selective fXa inhibitors. Furthermore, these new agents prevent the thrombus formation induced by the AV shunt in rabbits and may, therefore, be clinically useful as antithrombotic agents.
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Acknowledgments |
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We thank Drs. M. Thoolen and A. Slee for helpful comments; R. Carney for plasma levels determination; A. Liauw, C. Ellis, and J. Luettgen for technical assistance; Drs. J. Duke and S. Rosenfeld for providing rTAP; and Dr. Q. Han for providing DX-9065a.
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Footnotes |
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Accepted for publication September 23, 1999.
Received for publication June 22, 1999.
Send reprint requests to: Dr. Pancras C. Wong, DuPont Pharmaceuticals Company, P.O. Box 80400, Wilmington, DE 19880-0400. E-mail: pancras.c.wong{at}dupontpharma.com
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Abbreviations |
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LMWH, low molecular weight heparin; fXa, factor Xa; APTT, activated partial thromboplastin time; AV, arteriovenous; AVST, arteriovenous shunt thrombosis; GP, glycoprotein; PT, prothrombin time; rTAP, recombinant tick anticoagulant peptide; tPA, tissue plasminogen activator.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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