Novel, potent non-covalent thrombin inhibitors incorporating P3-lactam scaffolds

Article abstract of DOI:10.1016/S0960-894X(02)00010-0

Evolution of P₁-argininal inhibitor prototypes led to a series of non-covalent P₃-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S₁, S₂, and S₃ specificity pockets of thrombin. Rigid P₁-arginine surrogates possessing a wide range of basicity (calcd pK_a's～neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.

Full text of DOI:10.1016/S0960-894X(02)00010-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 743–748
Novel, Potent Non-Covalent Thrombin Inhibitors
Incorporating P3-Lactam Scaffolds
Jonathan Z. Ho, Tony S. Gibson and J. Edward Semple*
Department of Medicinal Chemistry, Corvas International, Inc., 3030 Science Park Road, San Diego, CA 92121, USA
Received 30 October 2001; accepted 13 December 2001
Abstract—Evolution of P1-argininal inhibitor prototypes led to a series of non-covalent P3-7-membered lactam inhibitors 1a–w,
featuring novel peptidomimetic units that probe each of the S1, S2, and S3 specificity pockets of thrombin. Rigid P1-arginine sur-
rogates possessing a wide range of basicity (calcd pKa’sꢀneutral–14) were surveyed. The design, synthesis, and biological activity of
these targets are presented. # 2002 Elsevier Science Ltd. All rights reserved.
Thrombin (fIIa), a multifunctional serine protease with
trypsin-like specificity, plays a central role in hemostasis
by regulating the blood coagulation cascade and platelet
activation.1 It also promotes numerous cellular events
including chemotaxis, proliferation, extracellular matrix
turnover and the release of cytokines. These actions
have been implicated in tissue repair processes and in
the pathogenesis of inflammatory and fibroproliferative
disorders such as pulmonary fibrosis and athero-
sclerosis.2 Thrombin is formed by prothrombinase-
mediated (PTase, complex of fXa-fVa-phospholipid-
Ca+2) cleavage of the zymogen prothrombin following
tissue injury. Serving as the terminal enzyme of the
coagulation pathway, thrombin cleaves fibrinogen to
fibrin, which in combination with fXIII and platelets
aggregates to a gel-like matrix, ultimately leading to the
formation of blood clots.3 Thromboembolic diseases are
a major cause of morbidity and mortality in the indus-
trialized world. Limited efficacy and side effects
of common antithrombotic drugs including heparin,
Figure 1. Design of P3-lactam thrombin inhibitors 1a–w.
*Corresponding author. Tel.: +1-858-455-9800 x1140; fax: +1-858-455-7895; e-mail: ed_semple@corvas.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00010-0

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J. Z. Ho et al. / Bioorg. Med. Chem. Lett. 12 (2002) 743–748
listed in Figure 2 in order of decreasing basicity and are
identified by the indicated acronyms (see SAR Table 1).
The calculated pKa values13 for several prototypical P1
arginine surrogates are listed and range from the highly
basic cyclic guanidine (GuanPip) through the essentially
non-basic indazole (H-bond donor). Novel peptide
mimics that probe the S1, S2, and S3 specificity pockets
of thrombin comprise the resultant targets. Several
potent and selective thrombin inhibitors resulted from
this exercise.
Synthetic routes to the rigid P1-arginine mimic pre-
cursors are outlined in Schemes 1 and 2.14 4-Amidino-
benzyl intermediates 2, 3, and 4 were prepared from p-
cyanobenzyl bromide by straightforward, high-yielding
methods. 2-Fluoro-4-amidinobenzylamine intermediate
6 was assembled in six steps in satisfactory overall yield
from commercial 4-bromo-2-fluoro-toluene via benzyl
azide 5. N-Boc-protected aminopyridine 74c and cyclo-
hexylamine 815 were prepared in three steps and five
steps, respectively, following literature protocols. Guani-
dine 9 was commercially available from AstaTech, Inc.
Figure 2. Acronyms and calculated pKa values for representative
rigidified P1-arginine surrogates.
warfarin, and aspirin has provided an impetus for the
development of alternate classes of antithrombotic
agents.4 Thus, direct inhibitors of thrombin, factor Xa
(fXa) and prothrombinase (PTase) are deemed attrac-
tive targets for therapeutic intervention.4,5 In this letter,
we detail our foray into the design, synthesis, and SAR
study of non-covalent thrombin inhibitors that resulted
in the identification of the novel, potent P3-lactam-P1-
arginine mimics 1a–w.6
We recently described new classes of peptidomimetic P1-
argininals as thrombin7 and factor Xa8 inhibitors that
incorporated lactam and heterocyclic scaffolds at the P3-
position. Several potent, selective, and orally bioavail-
able transition-state inhibitors emerged from this work.
The prototypical 7-membered lactams CVS 1778 and
CVS 2097 (Fig. 1) showed superior in vitro potency
against thrombin, selectivity towards other important
serine proteases, and demonstrated 66 and 67% oral
bioavailability in fasted dogs, respectively.7c,9 Although
these candidates showed interesting biological profiles,
the presence of the P1-argininal moiety posed problems
with regard to scale-up, purification, and long-term
configurational stability. Furthermore, the high basicity
of the guanidine function (pKa ꢀ12.5) negatively
impacted the pharmacokinetic (PK) profiles of some of
these inhibitors by making them susceptible to active or
‘facilitated’ intestinal transport mechanisms.10 This
mode of drug transport may lead to undesirable food
effects and rapid excretion, often resulting in sub-opti-
mal drug plasma levels and relatively short half-lives
(typically 1 to 4 h for P1-argininals).11
Scheme 1. Reagents and conditions: (a) NaN3, DMF, rt, 5 h, 96%; (b)
H2, Pd/C, EtOAc, 45 psi, 11 h, 93%; (c) NH2OHꢁ HCl, NMM, MeOH,
rt, 3 days, 89%; (d) H2, Pd/C, MeOH, 45 psi, 11 h, 99%; (e) CuCN,
DMF, reflux, 11 h, 58%; (f) NBS, (PhCOO)2, CCl4, reflux, 14 h, 42%;
(g) NaN3, DMF, rt, 20 h, 86–90%; (h) NH2OHꢁ HCl, NMM, MeOH,
rt, 3 days, 82%; (i) n-PrI, Cs2CO3, DMF, 50 ꢂC, 20 h, 62%; (j) Ph3P,
THF, rt, 20 h, 77–89% (k) 3 steps, see ref 4c; (l) 5 steps, see ref 15.
The P1-amidinothiophene precursors 11 and 12 were
constructed by a nine-step sequence as outlined in
Scheme 2. Using conventional methodology, 2-methyl-
thiophene was elaborated over 7 steps to provide multi-
gram lots of the P1-hydroxyamidine intermediate 10.
Direct catalytic reduction of 10 and N-deprotection led
to the parent amidinothiophene P1-intermediate 11.
Alternatively, 10 was cleanly O-alkylated and N-depro-
tected to afford the convenient precursor 12 in high
yield.
SAR, modeling, and topographic considerations of our
lead series led us to design and prepare the non-covalent
P3-lactam inhibitor prototypes 1a–w. As summarized in
Figure 1, our approach was to judiciously combine
intrinsically potent P4-sulfonamido-P3-lactam arrays
with rigidified P1-mono- and bicyclic arginine surro-
gates12 possessing a wide range of basicity (calcd
pKa’sꢀneutral–14). Arginine mimics investigated are

J. Z. Ho et al. / Bioorg. Med. Chem. Lett. 12 (2002) 743–748
745
hydroxylamine to provide P1-hydroxyamidine 1u (Table
1), and catalytic reduction afforded the target 1t.
Scheme 2. Reagents and conditions: (a) NBS, CCl4, HClO4, 84%; (b)
CuCN, DMF, reflux, 4 h, 87%; (c) NBS, AIBN, CCl4, reflux, 5 h,
91%–quant; (d) NaN3, DMF, rt, 10 h, 83%–quant.; (e) Ph3P, THF,
ꢂ
H2O , 0 C to rt, 94%; (f) Boc2O , KCO3, dioxane, H2O, rt, 12 h, 56%;
2
(g) NH2OHꢁ HCl, NMM, MeOH, rt, 12 h, 86%; (h) H2, Pd/C, MeOH,
45 psi, 10 h, 94%; (i) 4 M HCl, dioxane, 0 ꢂC to rt, 3 h, 84%; (j) n-PrI,
Cs2CO3, DMF, rt, 10 h; (k) 4 M HCl, dioxane, 0 ꢂC to rt, 3 h, 81%
overall.
Scheme 4. Reagents and conditions: (a) NH2OHꢁ HCl, NaOAc,
EtOH, rt to reflux, 95%; (b) PPA, 115 ꢂC, 5 min, 50–70%; (c) TMSCl,
TMEDA, NaI, CH3CN, À5 ꢂC; (d) I2, À5 ꢂC to rt, 95%; (e) NH3, aq
EtOH, 0 ꢂC to rt, 70–80%; (f) l-Pyroglutamic acid, 95% aq i-PrOH,
reflux; concd NH4OH, 40–45%, or via racemization-resolution:
l-Pyroglutamic acid, 95% aq i-PrOH, 5-NO2-salicylaldehyde, 70 ꢂC, 2
Assembly of the P3-azepinonecarboxylic acid inter-
mediates 13a–f and elaboration to targets 1a–s is
summarized in Scheme 3 (note: DHBF=2,3-dihydro-
benzofuran-5-yl). Following a variation of our pub-
lished protocol,7,9 e-aminocaprolactam was converted in
4 steps and in satisfactory overall yield to benzyl esters
13a–f. Ester hydrogenolysis delivered the corresponding
carboxylic acids, which were coupled with the appro-
priate P1-arginine precursors 2–12 and the resultant
penultimate intermediates were either N-deprotected or
reduced to provide the desired final targets 1a–s.
Representative deprotection conditions are summarized
in Scheme 3 and illustrate the breadth of chemistry used
for completion of the targets 1c,e,i,k,p,r,s.
days, 80–85% (ꢀ98% ee); (g) Boc2O , NaCO3, dioxane, H2O, rt, 18 h,
2
99%; (h) LiHMDS, THF, 0 ꢂC, BrCH2CO2Bn, 0 ꢂC to rt, 92%; (i) 5 M
HCl, EtOAc, 0 ꢂC to rt, ꢀquant.; (j) 2,3-dihydrobenzofuran-5-sulfo-
nyl chloride, NMM, DMF, rt, 57%; (k) H2, Pd/C, MeOH, 45 psi, 3 h,
97%; (l) 4-cyanobenzylamine, EDC, HOBt, NMM, DMF, 83%; (m)
.
NH2OH HCl, NMM, MeOH, rt, 10 h, 51% (1u); (n) H2, Pd/C,
MeOH, 45 psi, 2 days; RP-HPLC purification, 49%.
Fmoc-aminohexahydroazepinoindole-4-one-2-carboxylic
acid, (Fmoc-Haic-OH)18 serving as the starting material
for the P2-P3-tricyclic ‘Haic’ target 1w, was purchased
from Neosystem Laboratories, Strasbourg, France. This
material was elaborated via similar approaches (ester-
ification, N-deprotection, sulfonylation, hydrolysis, cou-
pling with 2, reaction with HONH2, hydrogenolysis,
RP-HPLC purification) to the target 1w in satisfactory
overall yield.
Scheme 3. Reagents and conditions: (a) Boc2O , KCO3, THF, rt, 18 h,
2
99%; (b) LiHMDS, THF, 35 ꢂC; BrCH2CO2Bn, 0 ꢂC to rt, 15 h, 97%;
(c) 5 M HCl, EtOAc, 0 ꢂC to rt,ꢀquant.; (d) R4SO2Cl, Et3N or NMM,
CH3CN, 0 ꢂC to rt, 29–83%; (e) H2, Pd/C, MeOH:toluene (3:1), 45
psi, 12–24 h, 62% toꢀquant.; (f) couple P1-amine: NMM, DMF, rt,
7–14 h, BOP or EDC/HOBt, 45–99%; (g) deprotect P1-group: for 1c:
H2, Pd/C, MeOH, 45 psi, 13 h, RP-HPLC, 65%; for 1e: Zn, HOAc, rt,
2 h; RP-HPLC, 44% overall; for 1i: Zn, HOAc, rt, 2 h; RP-HPLC,
70%; for 1p: TFA, CH2Cl2, 50 ꢂC, 30 min, RP-HPLC, 59% overall;
for 1r: 5 M HCl, EtOAc, rt, 2 h, RP-HPLC, 77% overall; for 1s: 4 M
HCl, dioxane, rt 2 h, RP-HPLC, 26%.
The in vitro biological activity of 23 non-covalent tar-
gets 1a–w along with the argininal standards CVS 1778
and CVS 20977c,9 is summarized in Table 1. All targets
were inactive on the thrombolytic enzymes plasmin, tis-
sue plasminogen activator (tPA) and urokinase plasmi-
nogen activator (uPA) as well as activated protein C
(PCa). CVS 1778 and CVS 2097 were potent inhibitors
of thrombin in vitro, exhibiting good selectivity against
factor Xa and moderate selectivity against trypsin
(trypn). Moderate to excellent levels of thrombin inhi-
bitory potency were observed for several new targets,
with Ki’s=0.6–61 nM for our leading candidates. Tar-
gets of greatest interest in terms of activity and/or
selectivity profiles include 1b, 1c, 1f, 1i (most potent), 1k
(good potency, high trypsin selectivity), 1p (moderate
potency, highest trypsin selectivity), 1v, and 1w.
Synthesis of the benzolactam target 1t is outlined in
Scheme 4. a-Tetralone was converted to 14 via the fol-
lowing 7-step protocol. Beckmann rearrangement of the
requisite oxime intermediate,16 three-step elaboration to
racemic 3-aminobenzolactam, classical resolution or
‘racemization-resolution’ (preferred),8d,17 followed by
protection of the resultant chiral amine intermediate
delivered optically pure 14 in multigram lots. Employ-
ing similar methodology as described above, inter-
mediate 14 was elaborated over four steps to carboxylic
acid 15. Standard EDC-HOBt mediated coupling of 15
with amine 2, reaction of the resultant P1-nitrile with

746
J. Z. Ho et al. / Bioorg. Med. Chem. Lett. 12 (2002) 743–748
Table 1. In vitro activity of non-covalent P3-lactam thrombin inhibitors 1a–w (R4SO2-P3-P2-P1)
Compd
R4SO2À
P3-P2
P1
Ki Values (nM)a
FXa Trypn
FIIa
Trypn/FIIa
Reference Covalent Inhibitors
CVS 1778
CVS 2097
BnSO2
(2-CO2Me)-BnSO2
7-Lac
7-Lac
Arg-al
Arg-al
0.54
0.95
40
93
18.0
16.0
33.3
16.8
Non-Covalent Targets
1a
1b
1c
1d
1e
1f
1g
1h
1i
PhSO2
BnSO2
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
7-Lac
6-Lac
7-Lac
7-Lac
7-Lac
AmdnBnAm
AmdnBnAm
AmdnBnAm
OHAmdnBnAm
FAmdnBnAm
AmdnBnAm
AmdnBnAm
AmdnBnAm
AmdnTpn
19.4
19.4
6.2
239.7
29.8
9.0
13.3
163.5
0.6
71.4
23.8
85.7
166.7
>338
315.0
8.3
84.6
3.2
80.5
7.6
35.2
11.6
12.3
5.9
1678.0
872.5
0.4
4.4
0.5
0.3
0.3
3.9
0.9
0.1
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
2,5-diOMePhSO2
3,4-diOMePhSO2
2-NaphSO2
5-(2,3-DHBenzofuran)SO2
PhSO2
>338
Inact.
>338
>338
>338
>338
52.7
10.7
23.5
36.7
>19.6
1j
GuanPip
GuanPip
GuanPip
GuanPip
AmMePyr
AmMePyr
AmMePyr
AmChx
ArnChx
Indazole
>338
Inact.
>338
Inact.
Inact.
Inact.
>338
Inact.
Inact.
Inact.
>338
Inact.
Inact.
1k
11
1m
1n
1o
1p
1q
1r
1s
1t
5-(2,3-DHBenzofuran)SO2
3,4-diOMePhSO2
2,5-diOMePhSO2
>1678
Inact.
>1678
1678.0
1678.0
Inact.
>1678
Inact.
19.5
BnSO2
BnSO2
>397
ꢀ4.2
18.0
42.5
92.9
39.5
195.2
53.2
282.5
14.4
>397
5-(2,3-DH Benzofuran)SO2
BnSO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
5-(2,3-DH Benzofuran)SO2
7-Lac
7-Lac
>31.5
Benzo-7-Lac
Benzo-7-Lac
Benzo-7-Lac
Haic
AmdnBnAm
OHAmdnBn Am
GuanPip
1.4
1u
1v
1w
Inact.
Inact.
2.5
61.0
10.8
Good
0.2
AmdnBnAm
49.2
aInhibition constants (Ki) of compounds 1a–w are derived from the corresponding IC50 values necessary to inhibit human thrombin (FIIa), factor
Xa (FXa), and trypsin cleavage of the chromogenic substrates described in ref 8 by 50%. Reported values for each compound are from a single IC50
determination that confirmed the initial range values.
In the most widely explored P4-dihydrobenzofuran-
sulfonyl-P3-azepinone series, in vitro potency decreased
as a function of the P1 arginine surrogate in the follow-
ing order: AmdnTpn (1i, Ki=0.6 nM, pKa=10.3)
>AmdnBnAm (1c, Ki=6.2 nM, pKa=10.2)>GuanPip
(1k, Ki=23.8 nM, pKa=14.1)>FAmdnBnAm (1e,
Ki=29.8 nM, pKa=9.4)>AmMePyr (1p, Ki=39.5 nM,
pKa=7.3)>AmChx (1r, Ki=53.2 nM, pKa=10.5)
>OHAmdnBnAm (1d, Ki=239.7 nM, pKa=4.2)
>Indazole (1s, Ki=282.5 nM, ꢀnon-basic, H-bond
donor). In this series, trypsin selectivity decreased as
a function of the P1 arginine surrogate in the follow-
ing order: AmMePyr (1p, trypn/fIIa=42.5)>GuanPip
(1k, trypn/fIIa=36.7)>AmChx (1r, trypn/fIIa>31.5)
>AmdnTpn (1i, trypn/fIIa=10.7)> >AmdnBnAm (1c,
trypn/fIIa=0.5)>FAmdnBnAm (1e, trypn/fIIa=0.3)
>OHAmdnBnAm (1d, trypn/fIIa=0.3). Indazole deriva-
tive 1s (FIIa Ki=282.5 nM) was inactive on trypsin but was
excluded from the ranking due to poor inhibitor
potency.
Ki=14.4 nM). The relative potency and selectivity
profiles of 1a–w may be rationalized from modeling
considerations which suggest numerous energetically
favorable interactions throughout the active site P4–P1
manifold, including b-sheet (Gly216), hydrophobic,
van der Waals and aromatic edge-to-face types of
interactions (S3 pocket plus 60 loop in S2 pocket, Fig.
1). Binding to thrombin probably occurs in a normal
substrate-like mode, with the P1-arginine surrogates
participating in salt bridge and/or water-mediated
hydrogen-bonding interactions with Asp189 in the S1
pocket.7À9 Other putative stabilizing interactions
between P1 and the S1 specificity pocket include van der
Waals interactions with Val213 and hydrogen bonds
with Gly219, Gly193 and Tyr 228.4a,cÀe Further discus-
sions along these lines will be included in a forthcoming
communication.
Oral dosing of several leading non covalent inhibitor
candidates at 1 mg/kg in dog cassette studies indicated
generally mediocre PK profiles. Low plasma concentra-
tions (Cmax ꢀ0.05–0.2 mg/mL), modest AUC values
(ꢀ25–50 mg min/mL), and short half-lives (t1/2 ꢀ35–
100 min) suggested only low levels of oral bioavail-
ability in this series.
Regarding SAR of the P2-lactam system with a fixed
P1-amidinobenzylamide residue, in vitro potency
decreased in the following order: 7-Lac (1c, Ki=6.2
nM)>Haic (1w, Ki=10.8 nM)>Benzo-7-Lac (1t,

J. Z. Ho et al. / Bioorg. Med. Chem. Lett. 12 (2002) 743–748
747
Starting with the reference lactam sulfonamides CVS
1778 and CVS 2097, rational design strategies generated
a series of 23 novel non covalent P3-lactam-P1-arginine
surrogates 1a–w. These targets probed the S3 specificity
pocket with six sulfonamide residues, the S2 pocket with
three peptidomimetic P2–P3 (fused) lactam moieties, and
the S1 pocket with eight rigid arginine surrogates of
varying size, shape and basicity.
Ambler, J.; Butler, K.; Dunnet, K.; Mitchelson, A.; Talbot,
M.; Tweed, M.; Wolls, N. Bioorg. Med. Chem. Lett. 2000, 10,
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In vitro evaluation against serine proteases involved in
the blood coagulation cascade and trypsin led to the
identification of several potent and moderately selective
thrombin inhibitors. The P3-azepinone-P1-amidinothio-
phene derivative 1i (AmdnTpn, Ki=0.6 nM, pKa=10.3)
was the most potent candidate prepared, while the P3-
azepinone-P1-aminomethylpyridine derivative 1p (Am-
MePyr, Ki=39.5 nM, trypn/fIIa=42.5) was the most
trypsin-selective. Numerous active site interactions cou-
pled with optimal P1-binding and presentation modes
are important for conferring good thrombin inhibitory
potency and trypsin selectivity in this class.
5. (a) Recent reviews: Coburn, C. A. Exp. Opin. Ther. Pat.
2001, 11, 721. (b) Vacca, J. P. Curr. Opin. Chem. Biol. 2000, 4,
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Acknowledgements
7. (a) Recent Corvas FIIa inhibitors: Minami, N. K.; ; Reiner,
J. E.; Semple, J. E. Bioorg. Med. Chem. Lett. 1999, 9, 2625. (b)
Reiner, J. E.; Lim-Wilby, M. S.; Brunck, T. K.; Uong, T. H.;
Goldman, E. A.; Abelman, M. A.; Nutt, R. F.; Semple, J. E.;
Tamura, S. Y. Bioorg. Med. Chem. Lett. 1999, 9, 895. (c)
Owens, T. D.; Semple, J. E. Bioorg. Med. Chem. Lett. 1998, 8,
3683. (d) Semple, J. E.; Rowley, D. C.; Owens, T. D.; Minami,
N. K.; Uong, T. H.; Brunck, T. K. Bioorg. Med. Chem. Lett.
1998, 8, 3525. (e) Semple, J. E. Tetrahedron Lett. 1998, 39,
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8. (a) Recent Corvas FXa Inhibitors: Semple, J. E.; Levy,
O. E.; Minami, N. K.; Owens, T. D.; Siev, D. V. Bioorg. Med.
Chem. Lett. 2000, 10, 2305. (b) Tamura, S. Y.; Levy, O. E.;
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Semple, J. E. Bioorg. Med. Chem. Lett. 2000, 10, 745. (c) Ho,
J. Z.; Levy, O. E.; Gibson, T. S.; Nguyen, K.; Semple, J. E.
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We gratefully acknowledge S. M. Anderson, L. Truong,
and P. W. Bergum for all in vitro pharmacological
studies, T. G. Nolan for analytical support, and J. E.
Reiner, J. J. Cui, G. L. Araldi, and D. V. Siev for sti-
mulating discussions regarding non-covalent antith-
rombotic inhibitor targets.
References and Notes
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748
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