Design and synthesis of phenylpyrrolidine phenylglycinamides as highly potent and selective TF-FVIIa inhibitors

Article abstract of DOI:10.1021/ml400453z

Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benz

Full text of DOI:10.1021/ml400453z

Letter
pubs.acs.org/acsmedchemlett
Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As
Highly Potent and Selective TF-FVIIa Inhibitors
Xiaojun Zhang,*,† Wen Jiang,† Swanee Jacutin-Porte,† Peter W. Glunz,† Yan Zou,† Xuhong Cheng,†
Alexandra H. Nirschl,† Nicholas R. Wurtz,† Joseph M. Luettgen,† Alan R. Rendina,† Gang Luo,†
Timothy M. Harper,† Anzhi Wei,‡ Rushith Anumula,§ Daniel L. Cheney,† Robert M. Knabb,‡
Pancras C. Wong,† Ruth R. Wexler,† and E. Scott Priestley†
†Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States
‡Bristol-Myers Squibb R&D, US Route 206 & Province Line Road, Princeton, New Jersey 08543-4000, United States
§Biocon BMS R&D Center (BBRC), Syngene International Ltd., Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road,
Bangalore 560 099, India
S
* Supporting Information
ABSTRACT: Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel
anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis
of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to
possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by
X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but
promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the
pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious
TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of
distribution, and a short t1/2 in dog PK studies.
KEYWORDS: TF-FVIIa inhibitor, anticoagulant, aminoisoquinoline, phenylpyrrolidine, phenylglycinamide, structure-based drug design
hromboembolic disorders are the most common cause of
replacement of the benzamidine P1 group with a less basic
Tmorbility and disability in the western world. Thrombus aminoisoquinoline in an acylsulfonamide series (Figure 1).14
1
formation is initiated via the extrinsic coagulation cascade by
exposure of tissue factor (TF) to circulating coagulation factor
VIIa (FVIIa) in blood. Binding of TF to FVIIa, a serine
protease, leads to a large enhancement of its catalytic activity.2
The TF-FVIIa complex initiates the extrinsic coagulation
pathway by activating factor IX to IXa and factor X to Xa,
which in turn activates prothrombin to thrombin. Thrombin
cleaves fibrinogen to fibrin and activates platelets, triggering
clot formation.3,4 Inappropriate clot formation in blood vessels
causes cardiovascular diseases such as ischemic stroke,
myocardial infarction, and deep venous thrombosis. Recent
Figure 1. Phenylglycine acylsulfonamide 1 vs benzylamide 2.
preclinical studies have shown that selective inhibition of the
Aminoisoquinoline acylsulfonamide 1 retained good potency
against TF-FVIIa with a Ki of 11 nM but showed poor Caco-2
permeability and low oral bioavailability in dogs (3.5%) and rats
(<1%). The poor permeability of compound 1 is likely due to
its zwitterionic nature (measured pKa: 3.1 and 8.9). We
reasoned that replacing the acidic acylsulfonamide with a
neutral benzylamide may improve the permeability and thus
oral bioavailability. The corresponding benzylamide 2 indeed
displayed improved Caco-2 permeability and oral bioavailability
in dogs and rats compared to acylsulfonamide 1. Although the
TF-FVIIa complex provides effective anticoagulation with a low
risk of bleeding.5−9 Herein, we report the design and synthesis
of phenylpyrrolidine phenylglycinamides as highly potent and
selective TF-FVIIa inhibitors with promising oral bioavailability.
One of the major challenges in the development of small
molecule drugs inhibiting TF-VIIa is achieving oral bioavail-
ability; the majority of the reported TF-FVIIa inhibitors have a
highly basic benzamidine P1 moiety (pKa ≈ 12).10 The
benzamidine forms a strong salt bridge interaction with Asp189
in the active site of the enzyme, resulting in inhibitors that are
potent, but poorly orally bioavailable due to protonation and
low permeability under physiological conditions. Some reports
of weakly potent nonbenzamidine TF-FVIIa inhibitors have
appeared in the literature.11−13 We reported successful
Received: November 7, 2013
Accepted: December 26, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ml400453z | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
potency of benzylamide 2 is significantly reduced, we
considered it to be a good lead that warranted further
optimization.
Our initial strategy to improve the potency of benzylamide 2
was to optimize the interactions with the S′ site15 in analogy to
that of the acylsulfonamide series by investigating substitution
on the benzyl group.14 The general synthesis of analogues of
compound 2 is shown in Scheme 1. A three component Petasis
improved potency by 30-fold, while other polar groups such as
NHSO2NH2 (7c), SO2NH2 (7d), NHCO2Me (7e), OH (7f),
and NH2 (7g) also improved potency and selectivity compared
to the 7a. These results indicate a strong preference for TF-
FVIIa to bind small polar groups at the meta-position of the P′
phenyl. The presence of an H-bond donor (NH or OH) is
important, as the N-methylation of 7b resulted in an inactive
compound 7h. Although these polar groups improved potency,
they afforded compounds that showed no PAMPA perme-
ability.
a
Scheme 1. Synthesis of Compound 7 and Analogues
Improvement of potency relative to 7a was also achieved
with substituents at the ortho-position of the P′ phenyl, as
observed in the corresponding acylsulfonamide series.14 Small
alkylsulfones (7i−k) were particularly effective, improving
potency by more than 30-fold relative to 7a. These sulfones
also showed low but measurable PAMPA permeability.
X-ray cocrystal structures of compounds 7d and 7j with TF-
FVIIa were obtained and are shown overlaid in Figure 2.19 As
expected, the aminoisoquinoline group forms a salt bridge
interaction with Asp189 in the S1 pocket. The 6-amino group
(NH) of the aminoisoquinoline and the carbonyl (CO) of the
amide form polar contacts with Ser195 and His57. The ethoxy
from the P2 phenyl engages a small hydrophobic pocket
defined in part by Thr98−Thr99 backbone and His57 side
chain. The benzylamide phenyl is projected into the S′ pocket.
The sulfonamide in 7d forms an intermolecular H-bond to a
structural water molecule bridging Asp60 side chain and Thr98
backbone oxygen. Similar hydrophilic interactions with TF-
FVIIa were observed for other reported TF-FVIIa inhib-
itors,14,20 However, the isopropylsulfone in 7j was shown to
engage in hydrophobic interaction with the Cys42−Cys58
disulfide bridge. This interaction, which provided more than
30-fold potency improvement, was first observed in the
acylsulfonamide series.14
a
Reagents and conditions: (a) toluene/MeOH (5:1), 60 °C, 6 h, 78%;
(b) EDC, ArCH2NH2, CH2Cl2/DMF (2:1), 15−70%; (c) 4.0 HCl,
EtOAc/dioxane, >80%.
reaction of 6-aminoisoqunoline 3,16 (3-ethoxy-4-
isopropoxyphenyl)boronic acid 4, and glyoxylate 5 gave rise
to the phenylglycine derivative 6.17 Coupling of compound 6
with a substituted benzylamine followed by deprotection of the
Boc groups afforded compound 7 as a racemic mixture for
biological testing to determine in vitro potency, selectivity, and
permeability (Table 1). Chiral separation of key compounds
was carried out if further profiling was needed.
The parent benzylamide 7a showed moderate potency
against TF-FVIIa, weak activity against other coagulation serine
proteases (FXa, FXIa and thrombin), and moderate PAMPA
permeability (Table 1). A simple acetamide NHAc (7b)
Overlay of X-ray cocrystal structures of compound 7d with 7j
suggested 2,5-disubstitution could potentially combine the
meta hydrophilic and ortho hydrophobic interactions (Figure
2). A disubstituted benzylamide 7l was prepared and showed
a
Table 1. P′ SAR of Phenylglycine Benzylamide 7
compd
R
TF-FVIIa Ki (nM)
FXa Ki (nM)
FXIa Ki (nM)
thrombin Ki (nM)
PAMPA (nm/s)
7a
7b
7c
7d
7e
7f
H
930
27
5900
7200
4100
8100
6200
3900
1800
7600
3500
2800
8200
7200
3900
7800
13000
9500
8700
11000
7800
7900
6700
2400
2900
2800
12000
48
1
3-NHAc
11000
11000
11000
7900
3-NHSO2NH2
3-SO2NH2
3-NHCO2Me
3-OH
47
0
75
0
84
0
170
200
5400
12
11000
9700
0
7g
7h
7i
3-NH2
0
b
3-N(Me)Ac
2-SO2cPr
11000
6700
ND
26
12
9
7j
2-SO2iPr
17
11000
11000
4000
7k
7l
2-SO2Et
26
2-SO2Et, 5-NHAc
4.4
0
a
b
Kis for the indicated enzymes were determined by chromogenic substrate assays at 25 °C (n = 2).18 No data.
B
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ACS Medicinal Chemistry Letters
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a
Scheme 2. Synthesis of Compound 18a−i
Figure 2. Overlay of X-ray cocrystal structures of 7d and 7j. Graphics
were generated with PyMol.21
further improvement in potency compared to 7d and 7j with a
Ki of 4.4 nM (Table 1). Compound 7l is also highly selective
against factor Xa, XIa, and thrombin but shows no permeability.
We have successfully improved the potency and selectivity
for phenylglycine benzylamide 7a with substituents at the ortho
and meta positions of the P′ phenyl, but the PAMPA
permeability was sacrificed for the potency gain. Introducing
a methyl group in compound 7a to form a tertiary amide 8 did
not appear to affect the TF-FVIIa potency (Figure 3) but
a
Reagents and conditions: (a) Pd(PPh3)4, Na2CO3, 1,2-DME, 95 °C,
96%; (b) platinum oxide, H2, EtOH, 40 psi, 88%; (c) chiralpak AD;
(d) methyl chloroformate, pyridine, 0 °C; (e) 4.0 HCl, EtOAc/
dioxane, 95% for 2 steps; (f) microwave, 105 °C, 15 min, ACN/DMF
(2:1), 20−65%; (g) EDC, 15, CH2Cl2/DMF (2:1), 20−65%; (h) 4.0
HCl, EtOAc/dioxane, >80%; (i) chiral separation.
coupling of pyrrolyl boronic acid 11 and aryl bromide 12 gave
rise to 2-substituted pyrrole 13. Reduction of the pyrrole and
nitro groups with platinum oxide under hydrogen pressure gave
a substituted phenyl pyrrolidine in good yield. The racemic
mixture was separated with a chiralpak AD column at this stage,
the active (R)-enantiomer 14 was converted to methyl
carbamate, and the Boc groups were deprotected to give
intermediate 15. A Petasis reaction of 6-aminoisoqunoline 3,
boronic acid 16, and glyoxylate 5 gave rise to the phenylglycine
derivative 17. Coupling of compound 17 with intermediate 15,
followed by deprotection of Boc groups and chiral separation
afforded phenylpyrrolidine 18 for biological testing. The three
component Petasis reaction is particularly versatile in the P2
SAR investigation because a wide variety of phenyl boronic
acids are readily available.
Figure 3. Evolution of phenylpyrrolidine TF-FVIIa inhibitors.
Small alkoxyl, alkyl, Cl, and F substituted phenyl P2 all gave
potent and selective TF-FVIIa inhibitors (18a−i, Table 2). The
anticlotting activity of these potent compounds were evaluated
in a FVII deficient prothrombin time (dVII PT) assay.18
Compound 18c with a 3,4-dimethoxy phenyl P2 showed the
best activity (EC2x, 3.5 μM), but unfortunately it had a very low
PAMPA permeability (2.0 nm/s). Interestingly, 6-F substitu-
tion on P2 phenyl (18f−i) appeared to have a beneficial effect
on PAMPA permeability, with 3-OEt/6-F affording the best
combination (18i). Compound 18i showed excellent potency
(Ki, 1.9 nM), good anticlotting activity (EC2x, 9.5 μM),
excellent selectivity (>2000-fold against FXa, FXIa, and
thrombin), and good PAMPA permeability (140 nm/s). It is
also more than 300-fold selective against nine other serine
proteases.22 The pharmacokinetic properties of 18i were
improved the PAMPA permeability. Constraining the tertiary
benzylamide to its bioactive conformation with a pyrrolidine
ring gave phenyl pyrrolidine amide 9 (a mixture of 4
diastereoisomers) that improved potency and maintained
good PAMPA permeability relative to compounds 7a and 8.
Introducing the potency enhancing meta and ortho substituents
in compound 9 and chiral separation gave enantiomerically
pure compound 10 that showed excellent TF-FVIIa potency
(Ki of 1.8 nM), but a disappointing PAMPA permeability (7
nm/s).
Given the excellent potency demonstrated with compound
10, SAR was further explored in the P2 region. The synthesis of
P2 analogues of 10 is shown in Scheme 2. Suzuki−Miyaura
C
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ACS Medicinal Chemistry Letters
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Table 2. Phenylpyrrolidine P2 SAR
a
compd
R
TF-FVIIa Ki (nM)
dVII PT (EC2x, μM)
FXa Ki (nM)
FXIa Ki (nM)
thrombin Ki (nM)
PAMPA (nm/s)
18a
18b
18c
18d
18e
18f
H
14
19
19
3.5
15
11
12
11
9.5
9.5
6000
2900
9000
3700
6400
5400
5200
4500
5200
11000
11000
10000
2700
3400
6400
5600
4900
6700
3600
4400
5700
4400
58
3-OCHF2
4.5
1.8
1.2
1.1
2.1
2.2
1.9
1.9
7.0
2.0
25
3,4-di-OMe
3-OMe, 4-Cl
3-OMe, 4-F
3-Me, 6-F
11000
11000
11000
11000
7100
25
46
18g
18h
18i
3-OMe, 6-F
3-OEt, 4,6-di-F
3-OEt, 6-F
64
49
140
a
dVII PT: FVII deficient prothrombin time.18
evaluated (Table 3). It shows a high clearance but a promising
oral bioavailability in dogs and moderate clearance and oral
Table 3. Pharmacokinetic Profile of Compound 18i
a
b
PK
dog
rat
CL (mL/min/kg)
Vss (L/kg)
t1/2 (h)
41 17
4.2 3.3
2.2 0.8
45 33
26 8.1
5.6 2.1
4.9 1.1
F (%)
7.9 4.3
a
b
Dogs (n = 3) were dosed 0.2 mg/kg iv and 1.0 mg/kg po. Rats (n =
3) were dosed 0.5 mg/kg iv and 1.0 mg/kg po.
bioavailability in rats. Protein binding of compound 18i in
human plasma was measured to be 96.8%. A dose projection
based on potency, protein binding, and PK suggested
compound 18i was not suitable for further in vivo evaluation.
Despite compound 18i displaying an impressive selectivity
against a panel of 12 serine proteases, profiling revealed
promiscuous activity in an in vitro safety panel of receptors and
enzymes.23
Figure 4. Binding model of a pyrrolidine acid with Lys60A. Graphics
were generated with PyMol.21
To address the promiscuous activity in the in vitro safety
panel and to further improve the anticlotting activity, we sought
to install an acid on the pyrrolidine ring. We anticipated that we
could use an ester prodrug approach to obtain permeable
compounds. Molecular modeling of a simple phenylpyrrolidine
suggested a likely interaction between an acid on the
pyrrolidine and Lys60A (Figure 4).24 Phenylpyrrolidine acid
19 was prepared and showed excellent potency and anticlotting
activity with Ki of 0.9 nM and dVII PT EC2x of 1.5 μM (Table
4). The acid group on the pyrrolidine improved the anticlotting
activity by 6-fold compared to 18i. With an acid on the
pyrrolidine ring, removal of the methyl carbamate on the P′
phenyl still afforded potent TF-FVIIa inhibitors, e.g., a simple
acid 20 showed anticlotting activity similar to that of compound
19. Both compounds are highly selective against a panel of 11
other serine proteases and cytochrome P450 enzymes.25
Compound 20 revealed a clean profile in the in vitro safety
panel of receptors and enzymes. The acids are not permeable,
but the corresponding esters showed reasonable PAMPA
Table 4. Summary of Phenylpyrrolidine Acid 19 and 20
dVII PT
TF-FVIIa
compd Ki (nM)
(EC2x,
selectivity vs 11 other
serine proteases, fold PAMPA (nm/s)
μM)
19
0.9
1.5
>500
0, 80
(methyl ester)
20
5.6
2.2
>900
0, 56
(ethyl ester)
permeability (Table 4). Unfortunately, the parent acids did
not possess the desired pharmacokinetic profile for a pro-drug
D
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ACS Medicinal Chemistry Letters
Letter
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Normandin, D. E.; Hartl, K. S.; Rendina, A. R.; Barbera, F. A.;
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approach due to the short half-life. Compound 20 showed a
moderate clearance (14 mL/min/kg), very low Vss (0.65 L/kg),
and short t1/2 life (1.1 h) in dog iv PK studies.
In summary, a series of phenylglycine benzylamide TF-FVIIa
inhibitors was designed to improve permeability and oral
bioavailability of a zwitterionic phenylglycine acylsulfonamide
lead. Optimization of the benzylamide, guided by X-ray
crystallography and conformational constraint, lead to a potent
TF-FVIIa inhibitor 18i with promising oral bioavailability, but
promiscuous activity in an in vitro safety panel of receptors and
enzymes. Introducing an acid on the pyrrolidine ring resulted in
highly potent, selective TF-FVIIa inhibitors 19 and 20 with
improved anticlotting activity, and clean profile in an in vitro
safety panel of assays. The pyrrolidine acid 20 showed a
moderate clearance, low volume of distribution, and short t1/2
in dogs.
ASSOCIATED CONTENT
* Supporting Information
■
S
Syntheses and characterization data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(X.Z.) Tel: 609-818-5457. E-mail: xiaojun.zhang@bms.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Jeffrey M. Bozarth, Frank A. Barbera, Ge Zhang, and
the Lead Evaluation department for carrying out the in vitro
enzyme assays. We would also like to thank Atsu Apedo,
Gottfried Wenke, and the SPS group for carrying out chiral
separation and pKa measurement, as well as Steven Sheriff for
depositing the X-ray coordinates and data in the PDB.
(16) Zhang, X.; Nirschl, A. A.; Zou, Y.; Priestley, E. S. Preparation of
phenylglycinamide and pyridylglycinamide derivatives useful as
anticoagulants (Bristol-Myers Squibb): PCT Int. Appl.
WO2007002313, 2007.
(17) Petasis, N. A.; Zavialov, I. A. A new and practical synthesis of α-
amino Acids from alkenyl boronic acids. J. Am. Chem. Soc. 1997, 119,
445−446.
(18) For full experimental details of the biological assays, see ref 9.
(19) PDB deposition number is 4NG9 for TF-FVIIa-7d and 4NGA
for TF-FVIIa-7j.
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̈
(22) The nine serine proteases are FIXa, XIIa, plasma kallikrein,
chymotrypsin, trypsin, plasmin, TPA, urokinase, and activated protein
C.
(23) Nine enzymes and receptors in MDS Pharma’s in vitro safety
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drug concentration.
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E
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