Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity

Article abstract of DOI:10.1021/jm800180e

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is

Full text of DOI:10.1021/jm800180e

J. Med. Chem. 2008, 51, 3061–3064
3061
Discovery of a Novel, Orally Active
Himbacine-Based Thrombin Receptor
Antagonist (SCH 530348) with Potent
Antiplatelet Activity
Samuel Chackalamannil,* Yuguang Wang,
William J. Greenlee, Zhiyong Hu, Yan Xia, Ho-Sam Ahn,
George Boykow, Yunsheng Hsieh, Jairam Palamanda,
Jacqueline Agans-Fantuzzi, Stan Kurowski,
Michael Graziano, and Madhu Chintala
Figure 1. Himbacine-derived thrombin receptor antagonists. Com-
pound 4 is a fourth generation thrombin receptor antagonist with
exceptional oral antiplatelet effect.
Schering-Plough Research Institute, 2015 Galloping Hill Rd,
Kenilworth, New Jersey 07033
of bleeding. GpIIb/IIIa antagonists block the final common
pathway of aggregation of platelets independent of the mode
of activation. The currently available GpIIb/IIIa antagonists,
albeit potent, are intravenous formulations and efforts to achieve
safe, orally active agents based on this mechanism have
failed.21,22 Therefore, there exists an unmet clinical need for a
potent, orally active antiplatelet agent with a better safety profile.
The inhibition of thrombin-mediated platelet activation provides
such an opportunity.
ReceiVed February 20, 2008
Abstract: The discovery of an exceptionally potent series of thrombin
receptor (PAR-1) antagonists based on the natural product himbacine
is described. Optimization of this series has led to the discovery of 4
(SCH 530348), a potent, oral antiplatelet agent that is currently
undergoing Phase-III clinical trials for acute coronary syndrome
(unstable angina/non-ST segment elevation myocardial infarction) and
secondary prevention of cardiovascular events in high-risk patients.
Besides its central role in hemostasis and wound healing,
thrombin, the main effector protease of the coagulation cascade,
activates platelets and other cell types by proteolytic activation
of cell surface receptors known as protease activated receptors
(PARs). The proteolytic enzyme cleaves the extracellular loop
of the G-protein-coupled receptor (GPCR) and the newly
unmasked amino terminus acts as a “tethered ligand” that binds
to the proximally located transmembrane loop of the GPCR,
eliciting intracellular signaling.23–25 Four PARs are known:
PAR-1, PAR-2, PAR-3, and PAR-4. Among these, PAR-1, also
known as thrombin receptor, is widely distributed in human and
monkey platelets, endothelial cells, and smooth muscle cells.
Among the various platelet activating ligands, thrombin is the
most potent activator, and thrombin-mediated platelet aggrega-
tion plays a critical role in the pathophysiology of thrombosis.26
Therefore, a thrombin receptor antagonist is expected to produce
potent antiplatelet effects. Additionally, because thrombin-
mediated fibrin generation is unaffected, such an agent is likely
to have less bleeding liability than conventional antithrombotic
agents.27,28 Because thrombin is known to be mitogenic in
endothelial and smooth muscle cells via the PAR-1 mechanism,
a PAR-1 antagonist may have additional therapeutic utility in
the treatment of vascular disorders such as atherosclerosis and
restenosis that often occurs following surgical interventions.29
We have previously reported the discovery of PAR-1
antagonists 1–3 based on a lead generated from the natural
product himbacine (5) (Figure 1).30–33 These compounds bind
to PAR-1 in a competitive manner with high affinity and are
highly active in a series of functional assays that measure cellular
responses to platelet activation. More importantly, these com-
pounds showed robust inhibition of platelet aggregation in an
ex vivo cynomolgus monkey model following oral administra-
tion. As reported earlier, the ent-himbacine absolute stereo-
chemistry for the tricyclic region is preferred for the himbacine-
derived PAR-1 antagonists.
Coronary artery disease (CAD)a is the leading cause of
cardiovascular death in the Western world.1–3 Acute clinical
manifestations of CAD are triggered by rupture of a vulnerable
atherosclerotic plaque.4–6 The subsequent thrombotic events lead
to a spectrum of clinical conditions known as acute coronary
syndrome (ACS), which include Q-wave and non-Q-wave
myocardial infarctions and unstable angina.7–9 Therapeutic
management of ACS includes percutaneous coronary interven-
tion (PCI) and pharmacological therapy using antithrombotic
agents.10–12 The currently available antithrombotic agents can
be classified as anticoagulants, antiplatelets, and fibrinolytic
agents. Anticoagulants are addressed to the coagulation cascade,
where their net effect is either to modulate the endogenous level
of thrombin or inhibit the enzymatic activity of thrombin.13,14
Antiplatelet agents inhibit platelet activation and aggregation,
a key process of hemostasis and clot formation.15,16 Fibrinolytic
agents work by lysis of existing clots.17
Platelets are activated by a variety of agonists such as
thrombin, adenosine diphosphate (ADP), thromboxane A2
(TxA2), epinephrine, collagen, etc.18 Antiplatelet agents inhibit
platelet activation via specific platelet surface receptors. Acti-
vated platelets undergo shape change, secrete granular contents,
and express activated glycoprotein IIb/IIIa (GpIIb/IIIa) receptors
on their surface, which bind to fibrinogen, causing platelet
aggregation.19,20 The currently available antiplatelet agents such
as aspirin (TxA2 biosynthesis inhibitor by cyclooxygenase-1
inhibition) and clopidogrel (ADP receptor antagonist) have
modest potency, and they are associated with an increased risk
* To whom correspondence should be addressed. Phone: 908-740-3474.
Fax: 908-740-7164. E-mail: samuel.chackalamannil@spcorp.com.
a Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery
disease; CYP, cytochrome P450; Gp, glycoprotein; GPCR, G-protoein
coupled receptor; haTRAP, high affinity thrombin receptor activating
peptide; HCASMC, human coronary artery smooth muscle cells; HPBCD,
hydroxypropyl-ꢀ-cyclodextrin; PCI, percutaneous coronary intervention;
PAR, protease-activated receptor; PRP, platelet rich plasma ; PT, prothrom-
bin time; APTT, activated partial thromboplastin time; TxA2, thromboxane
A2.
As part of our continuing effort to optimize the potency and
pharmacokinetic profile of this series, we have further explored
the C-7 region of the tricyclic motif, which has been known to
10.1021/jm800180e CCC: $40.75
2008 American Chemical Society
Published on Web 05/01/2008

3062 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Letters
Table 2. Oral Ex Vivo Results in Cynomolgus Monkey Model and
Scheme 1
Corresponding Monkey Pharmacokinetics Data
monkey PKb
AUC (µM·h),
Cmax (µM)
ex vivo platelet aggregation
compd
inhibition (duration)a n ) 3
6
8
9
<40% at 1 mg/kg (6 h)
100% at 1 mg/kg (24 h)
100% at 1 mg/kg (24 h)
55% at 1 mg/kg (24 h)
<40% at 1 mg/kg (6 h)
100% at 1 mg/kg (>24 h)
100% at 0.1 mg/kg (>24 h)
inactive at 0.5 mg/kg
NT
11.38, 0.75
5.53, 0.39
2.63, 0.26
NT
5.03, 0.33
0.20, 0.018
NT
0.20, 0.024
2.08, 0.20
0.13, 0.020
11
13
15
4
19
23
25
28
80% at 0.1 mg/kg (24 h)
80% at 0.1 mg/kg (24 h)
100% at 1 mg/kg (24 h)
Table 1. SAR of 7-Amino Derivativesa
a All compounds, as hydrochloride salts, were dosed in 0.4% methyl
cellulose (MC) except compound 6, which was dosed in 20% HPBCD. In
general, platelet aggregation inhibition <40% is considered insignificant
and >80% is considered robust. b AUC and Cmax are given for Ex Vivo
study animals (n ) 3); AUC(0-24h) for all compounds.
for the bulkier alkyl carbamates (e.g., 17 and 18) and secondary
carbamates with bulkier N-alkyl groups (19 vs 20).
The phenyl substitution pattern followed the previously
established paradigm. In general, ortho- and meta- halogen, CF3,
or CN substitution gave the best PAR-1 binding. Certain ortho,
meta-disubstitutions, as represented by 27 and 28, were also
tolerated.
Several compounds from each subset were screened in a
cynomolgus monkey ex vivo platelet aggregation inhibition
model. The data are given in Table 2 along with drug plasma
levels. The duration of platelet activity is noted in parenthesis.
In general, platelet aggregation inhibition of <40% is considered
insignificant at any time point and >80% inhibition of ex vivo
platelet aggregation is considered robust. In this efficacy model,
a more discriminating property was seen among various
compounds with excellent in vitro PAR-1 affinity.
The amine precursor 6 did not show any significant inhibition
of platelet aggregation. The amides 8 and 9 showed robust
inhibition of platelet aggregation at 1 mg/kg with 24 h duration.
However, at lower doses, these compounds had only insignifi-
cant activity (data not shown). The urea derivative 11 showed
only weak activity. Likewise, the sulfonamide 13 showed only
weak inhibition at the 6 h time point.
The carbamate derivatives showed a very promising profile.
At 1 mg/kg, the ethyl carbamates 15 and 4 showed 100%
inhibition of platelet aggregation for 24 h. Because we preferred
the m-fluoro-substituted compound 4 to the corresponding CF3-
substituted compound 15, due to its reduced lipophilicity, further
dose-down experiments were carried out on 4, sequentially, at
0.5, 0.3, 0.1, and 0.05 mg/kg. At all doses g0.1 mg/kg, we
noted 100% inhibition of platelet aggregation for 24 h (Figure
2). The 0.1 mg/kg study was repeated to monitor the recovery
of platelet activity. As shown in Figure 2, partial recovery of
platelet function was realized in 48 h.
Compound 4 was further profiled in a series of assays.
Scatchard plots of saturation binding in the presence and absence
of 4 were consistent with a competitive binding profile to the
PAR-1 receptor. To effectively compete against a tethered
ligand, an antagonist needs to have not only high affinity but
also it should have a slow dissociation from the receptor. In
kinetic studies, 4 showed a long dissociation t1/2 of about 20 h,
which explains the excellent ex vivo potency and long duration
of action for this compound.
Kib
compd
X
Y
(nM) ( SEM
6
7
8
NH2
m-F
20 ( 0.0
30 ( 8.5
6.4 ( 1.1
6.5 ( 0.9
6.2 ( 0.6
4.4 ( 0.5
4.8 ( 0.6
11 ( 2.1
10 ( 6.0
13 ( 3.2
8.1 ( 1.1
6.1 ( 0.9
17 ( 4.5
44 ( 8.0
4.1 ( 1.4
89 ( 20.5
3.7 ( 0.05
5.9 ( 0.3
11 ( 4.9
367 ( 98
1.8 ( 0.05
11 ( 5.6
5.9 ( 2.3
11 ( 4.0
NHCOMe
NHCOEt
m-CF3
m-F
9
NHCOCyPr
NHCOMe
NHCONHMe
NHCONHEt
NHSO2Me
NHSO2Me
NHCO2Et
NHCO2Et
NHCO2Me
NHCO2Pr
NHCO2t-Bu
NMeCO2Et
NPrCO2Et
NMeCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
m-F
m-F
m-F
m-F
10
11
12
13
14
15
4
16
17
18
19
20
21
22
23
24
25
26
27
28
m-F
m-CF3
m-CF3
m-F
m-F
m-F
m-CN
m-F
m-F
m-CF3
m-OMe
o-F
m- CONH2
m-CN
m-Cl
3,5-F,F
2-F,3-Me
a Absolute stereochemistry shown. 7-ꢀ-derivatives tested showed com-
parable Ki values; however, 7-R-derivatives were preferred due to their ease
of synthesis. b PAR-1 binding assay ligand: [3H]ha TRAP, 10 nM (Kd )
15 nM); n ) 9 for compound 4, and 2 for the rest.
undergo considerable in vivo metabolism.30 Toward this end,
various derivatives of the C-7 amine were explored. A repre-
sentative synthesis of these compounds is outlined in Scheme
1. The previously reported ketone 29 was subjected to reductive
amination to give the 7-R-amine-substituted tricyclic precursor
as the major diastereomer.30 Derivatization of the amine to the
corresponding amide, urea, sulfonamide, and carbamate was
achieved under standard conditions. In vitro binding studies were
carried out on human platelet membrane-derived PAR-1 using
radiolabeled high affinity thrombin receptor activating peptide
([3H]haTRAP) as ligand, according to the previous reports.34
The in vitro binding data are provided in Table 1. The primary
amine 6 inhibited PAR-1 with a Ki of 20 nM. The amides 7-10
showed excellent PAR-1 affinity. The urea (11 and 12) and
sulfonamide derivatives (13 and 14) also showed excellent
PAR-1 affinity. Similarly, the carbamates 4 and 15-28 were
very active. There was a general trend toward reduced affinity
The effect of 4 on aggregation responses to thrombin (10
nM), haTRAP (15 µM), ADP (20 µM), and collagen (5 µM) in

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3063
Table 3. Summary of In Vitro and Pharmacokinetic Data for Compound 4
PAR-1 Ki
8.1 nM
inhibition of human platelet aggregation (IC50)
47 nMa, 25 nMb
Ca2+ transient assay (Ki)c
1.1 nM
13 nM
proliferation assay (Ki)d
rat PK (oral)e: AUC(0-24h), Cmax, F; IV t(1/2)
5.3 (µM·h), 0.67 (µM), 33%; 5.1 h
10 (µM·h), 1.3 (µM), 86%; 13 h
monkey PK (oral)f: AUC(0-24h), Cmax, F; IV t(1/2)
a Induced by 10 nM thrombin. b Induced by 15 µM haTRAP. c Inhibition of thrombin-stimulated Ca2+ transient in HCASMC. d Inhibition of 3H thymidine
incorporation in HCASMC. e Oral and intravenous (IV) dosing of HCl salt at 10 mg/kg. f Oral and IV dosing of HCl salt at 1 mg/kg. Vehicle for oral dosing:
0.4% methyl cellulose; vehicle for IV dosing: 20% hydroxypropyl ꢀ-cyclodextrin.
the targeted period of 7 days. Because of its excellent safety
margin and superior potency, carbamate 4 was advanced to full
development.
In summary, our efforts in the thrombin receptor antagonist
area have culminated in the discovery of a highly potent
thrombin receptor antagonist 4. Compound 4 represents a fourth
generation thrombin receptor antagonist with a Ki of 8.1 nM.
The unique properties of 4 are underscored by its excellent oral
bioavailability in multiple species, its high potency in a series
of in vitro functional assays, and its potent oral activity in an
ex vivo cynomolgus monkey model of platelet aggregation.
Compound 4 was 30 times more potent than the initial
development candidate in the series, showing complete oblitera-
Figure 2. Inhibition of ex vivo haTRAP-induced platelet aggregation
tion of agonist induced platelet activation at 0.1 mg/kg with
>24 h duration of activity (versus comparable efficacy at 3 mg/
kg for the initial candidate).31 After successfully completing
phase-I and phase-II clinical studies, compound 4 has entered
phase-III clinical studies for acute coronary syndrome (unstable
angina/non-ST segment elevation myocardial infarction) and
secondary prevention of cardiovascular events in high-risk
patients.36
by 4 in cynomolgus monkeys (n ) 3) after oral administration.
Complete inhibition of platelet aggregation is achieved for 24 h post
dosing with partial recovery occurring at 48 h at 0.1 mg/kg. The
pharmacokinetic data suggests that only low plasma concentration is
required for robust platelet aggregation inhibition. Ex vivo platelet
aggregation to haTRAP was performed in whole blood using impedance
aggregometry.
human platelet-rich plasma (PRP) was evaluated in a compara-
tive experiment. The compound showed potent inhibition of
thrombin-induced platelet aggregation with an IC50 of 47 nM
and haTRAP-induced platelet aggregation with an IC50 of 25
nM, whereas it showed no inhibition of platelet aggregation
induced by other agonists such as ADP, collagen, a standard
thromboxane mimetic 9,11-dideoxy-11R,9R-epoxymethanopros-
taglandin F2R (U46619),35 and a PAR-4 agonist peptide.
In additional functional assays, compound 4 inhibited thrombin-
induced calcium transient in human coronary artery smooth
muscle cells (HCASMC) with a Ki of 1.1 nM (Table 3). It also
inhibited thrombin-stimulated thymidine incorporation in
HCASMC with a Ki of 13 nM. Pharmacokinetic profiling of 4
was done in rat and monkey models. Following oral administra-
tion, compound 4 was well absorbed in rat (68%; 10 mg/kg)
and in monkey (82%; 1 mg/kg) models. Tmax was observed at
about 3 h in rats and 1 h in monkeys. The elimination half-life
was 5.1 h in rats and 13 h in monkeys. The oral bioavailability
was 33% in rats and 86% in monkeys.
Acknowledgment. We acknowledge the support of Drs.
John Piwinski, Catherine Strader, Cecil Pickett, Ashit Ganguly,
John Hunter, Ronald White, Richard Morrison, Walter
Korfmacher, Prudence Bradley, Birendra Pramanik, Pradip
Das, T.-M. Chan, C. A. Evans, Mohindar Puar, T. K. Thiru-
vengadam, Jesse Wong, Jianshe Kong, David Hesk, and Paul
McNamara.
Supporting Information Available: Experimental procedures
for platelet aggregation studies, PAR-1 binding assay, and synthesis
and characterization of intermediates and selected final products.
This material is available free of charge via Internet at http://
pubs.acs.org.
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JM800180E