Structure and property based design of factor Xa inhibitors: Biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs

Article abstract of DOI:10.1016/j.bmcl.2007.11.019

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Full text of DOI:10.1016/j.bmcl.2007.11.019

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 28–33
Structure and property based design of factor Xa inhibitors: Biaryl
pyrrolidin-2-ones incorporating basic heterocyclic motifs
Robert J. Young,a,* Alan D. Borthwick,a David Brown,a Cynthia L. Burns-Kurtis,b
a
a
a
a
´
Matthew Campbell, Chuen Chan, Marie Charbaut, Maire A. Convery,
Hawa Diallo,a Eric Hortense,a,b Wendy R. Irving,a Henry A. Kelly,a N. Paul King,a
Savvas Kleanthous,a Andrew M. Mason,a Anthony J. Pateman,a
Angela N. Patikis,a Ivan L. Pinto,a Derek R. Pollard,a Stefan Senger,a Gita P. Shah,a
John R. Toomey,b Nigel S. Watson,a Helen E. Westona and Ping Zhoua
aGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
bGlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
Received 5 September 2007; revised 6 November 2007; accepted 8 November 2007
Available online 13 November 2007
Abstract—Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa
(fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities
and encouraging oral pharmacokinetic profiles.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The quest for safe and efficacious oral anticoagulant
therapies has presented numerous challenges to medici-
nal chemists as the search for potent and selective inhib-
itors of specific enzymes, such as Factor Xa (fXa), in the
blood coagulation cascade has proceeded.1 In the
accompanying paper,2 we have described the synthesis
and evaluation of a series of N-biaryl pyrrolidinones 1,
which produced a number of highly potent fXa inhibi-
tors. Whilst this series included molecules with encour-
aging pharmacokinetic profiles, coagulation was not
modulated at therapeutically useful concentrations in
spite of the excellent intrinsic potencies secured with
many examples.
pendant basic functionality,5 whilst seeking to exploit
other key drivers for intrinsic potency and physical
property optimisation.
F
H
N
O S
O
X
H
N
O S
O
N
N
R1
R1
Y
O
O
N
1
2
N
R2
N
R3
The good levels of potency achieved with unsubstituted
imidazole and pyrazole distal rings, as described in the
preceding paper,2 provided an excellent starting point
to make molecules of appropriate topology and reduced
hydrophobicity. In particular, a 2-substituted electron
deficient imidazole structure offered the opportunity to
place the relatively acidic proton on C5 in the correct ori-
entation to better exploit an interaction with the indole
fragment of Trp215 established by QSAR analysis. Fur-
thermore, as the presence of a substituent on the opposite
‘ortho’ position was clearly beneficial for enhancing fXa
activity, this was an attractive centre to incorporate a ba-
sic substituent. The initial programme of work targeted
We have previously reported on the positive impact of
reducing hydrophobicity towards securing better trans-
lation of intrinsic potency into anticoagulant activity.3
The effect of a basic substituent, as part of the P4 ligand,
was noted as a significant influence on both hydropho-
bicity and anticoagulant activity in our acyclic alanyl
amide series.4 In this paper, we further develop the
theme of a biaryl P4 motif to include the addition of
Keywords: Factor Xa; Oral inhibitors.
*
Corresponding author. Tel.: +44 1438 768372; fax: +44 1438
763620; e-mail: Rob.J.Young@gsk.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.019

R. J. Young et al. / Bioorg. Med. Chem. Lett. 18 (2008) 28–33
29
2-(dimethylamino)methyl-1H-imidazol-1-yl analogues 2
H
N
Boc
b
and was then expanded to other distal heterocycles to ex-
plore structure activity and structure property relation-
ships around this template (Fig. 1).
NH2
NH2
F
O
F
O
a
4
then, c
The target molecules were synthesised as outlined in
Scheme 1. Thus, 2-fluoro-4-iodo-aniline and N-Boc
homoserine lactone were converted into the key N-aryl
pyrrolidinone 3 as described previously, using trimethyl
aluminium followed by Mitsunobu methodology.2
Reductive amination reactions of appropriate amines
with commercial heterocyclic aldehydes furnished the
N-substituted aminomethyl heterocycles 4, which were
cross-coupled to give biaryl compounds 5 (and their posi-
tional isomers) under Ullman-type conditions.6 These
intermediates, which had racemised under the forcing
conditions, were deprotected by treatment with acid, fur-
nishing amines, which were converted into the requisite
sulfonamides 6 using our standard procedure.2,3
N
N
I
X = Y = CH;
Z = N
NMe2
R2 = R3 = Me
7
O
H
NH2
R1
N
S
O
O
F
O
N
N
N
N
d
F
8
9
NMe2
NMe2
N
N
Alternatively, an asymmetric synthesis was achieved
through the reaction of 2-(dimethylamino)methyl-imid-
azole with 2-fluoro-4-iodo-aniline to form the biaryl ani-
line 7, which was carried through the reaction sequence
via amine 8 to furnish chiral targets 9 with the preferred
(3S)-stereochemistry (vide infra) (Scheme 2).
Scheme 2. Chiral synthesis of target compounds. Reagents and
conditions: (a) CuI, 8-hydroxyquinoline, K2CO3, DMSO, 130 ꢁC; (b)
Me3Al, DCM, 0 ꢁC–rt; then DtBAD, Bu3P, THF, rt; (c) HCl, dioxane,
rt, (d) R1SO2Cl, pyridine, MeCN, rt.
coupling as outlined in Scheme 3. Thus, the iodoaryl
intermediate 3 was cross-coupled with ethoxycarbonyl
trimethylstannyl isoxazole to give 11,7 which was then
converted into the requisite amine 12 via hydrolysis,
reduction, bromination and displacement. Finally, the
racemic target compounds 10 were furnished by acid
deprotection and sulfonylation in the usual manner.
Additionally, analogues with related isoxazole carbon-
linked motif 10 were synthesised using a key Stille
H
N
H
N
CHO
a
X
Y
R3
X
Y
N
R2
Z
Z
4
X = N; Y = Z = CH or
X = Y = CH; Z = N or
X = Z = CH; Y = N
The initial set of 2-(dimethylamino)methyl-1H-imidazol-1-
yl derivatives, illustrated with fXa8 and anticoagulant activ-
ity (expressed at 1.5· PT)9 in Table 1, was designed to test
H
N
Boc
H
N
Boc
NH2
F
O
N
I
O
O
F
H
N
Boc
4, c
b
I
3
O
N
O
F
H
a
b, c, d
H
N
R1
Boc
N
S
O
3
11
SnMe3
O
O
O
O
N
N
N
OEt
OEt
d, e
F
F
O
N
O
N
6
5
N
O
H
X
R3
H
X
R3
N
N
Boc
N
R1
N
S
R2
Y
Z
R2
Y
Z
O
positional isomers also formed:
O
F
O
N
N
F
Ar
Ar
e, f
N
N
N
12
10
or
NMe2
N
NMe2
NMe2
NMe2
O
N
O
N
Scheme 1. Reagents and conditions: (a) R2R3NH, NaHB(OAc)3,
AcOH, THF, rt; (b) Me3Al, DCM, 0 ꢁC–rt; then DtBAD, Bu3P, THF,
rt; (c) CuI, 8-hydroxyquinoline, K2CO3, DMSO, 130 ꢁC; (d) HCl,
dioxane, rt; (e) R1SO2Cl, pyridine, MeCN, rt.
Scheme 3. Reagents and conditions: (a) Pd(PPh3)2Cl2, dioxane, D; (b)
LiBH4, THF, 0 ꢁC; (c) NBS, PPh3, DCM, rt; (d) Me2NH, THF, rt; (e)
HCl, MeOH, rt; (f) R1SO2Cl, pyridine, MeCN, rt.

30
R. J. Young et al. / Bioorg. Med. Chem. Lett. 18 (2008) 28–33
Table 1. fXa inhibitory activities,8 anticoagulant potency,9 measured hydrophobicity11a and human serum albumin binding data11b for compounds
13 to 21
H
N
N
F
R1
O
S
O
O
N
N
Me2N
Entry
R1
fXa Ki (nM)
1.5· PT (lM)
CHI LogD7.4
2.44
%HSA bound
nda
S
S
Cl
Cl
13
0.2
0.2
3.3
14
15
4.2
1.6
2.54
2.32
92.1
93.4
S
Cl
3.1
H
N
16
<1
6.6
1.98
94.6
Cl
17
18
19
0.6
0.8
2.3
19.2
11.6
43.2
2.55
2.58
2.75
94.7
96.8
97.9
Cl
S
S
Cl
Cl
S
N
S
20
21
4.5
5.9
45.4
25.4
2.59
1.76
96.3
93.2
Cl
Cl
N
H
a nd, not determined.
our hypotheses regarding the topology and connectivity of
the distal ring, utilising a range of P1 sulfonamides.3b
biaryl group, designed to fill the fXa S4 pocket, the
5-chlorothien-2-yl-based analogues 15 and 13, with ethyl
and propenyl linkers, respectively, were potent and
selective fXa inhibitors (>1000-fold and >100-fold
selective over thrombin, respectively). In contrast, incor-
poration of these P1 groups in our 1-methyl-2-morphol-
in-4-yl-2-oxoethyl series resulted in a potent selective
inhibitor of thrombin and potent dual inhibitor of
thrombin/fXa, respectively.10
Gratifyingly, sub-nanomolar inhibition of fXa was
achieved with many P1 variations, with potencies
broadly similar to those achieved with the non-basic
biaryl analogues reported in our accompanying paper.
However, of greater significance was the translation of
this potency into much improved anticoagulant activity.
The lower levels of plasma protein binding observed
most likely influenced this effect, although there was
no simple relationship between the conversion of intrin-
sic potency into anticoagulant activity and hydropho-
bicity linked plasma protein binding. It is also worth
highlighting that as a result of incorporating the bulky
Encouraged by these promising profiles, further sets of
compounds were generated to explore alternative topol-
ogy and connectivity in the distal rings and the optimal
position for the pendant (dimethylamino)methyl substi-
tuent (Table 2).

R. J. Young et al. / Bioorg. Med. Chem. Lett. 18 (2008) 28–33
31
Table 2. fXa inhibitory activities,8 anticoagulant potency9 and measured hydrophobicity data11a for isomeric diazoles 22 to 28
H
N
N
F
R1
O
S
O
O
Het
Entry
R1
Distal Het
fXa Ki (nM)
1.5· PT (lM)
CHI LogD7.4
2.31
S
Cl
N
22
<0.3
1.6
N
N
S
Cl
N
N
23
24
895
0.5
nda
3.35
3.29
N
S
S
Cl
Cl
17.1
N
O N
N
N
25
29.3
10.1
1.64
N
N
N
S
S
Cl
26
27
14.7
125
37.4
1.82
2.4
N
N
N
Cl
N
>100
N
S
Cl
N
28
14.7
23.5
2.2
N
a nd, not determined.
Table 3. Pharmacokinetic parameters of compounds 13, 14 and 15 in
male Sprague–Dawley rats following intravenous and oral
administration12
The SAR generated in Table 2 highlighted that the
topology of the ring was very important and supported
our hypothesis on the interaction of an acidic proton
with Trp215. Most strikingly, including the 2-(dimethyl-
amino)methyl group on the position ortho to the ring
junction conferred greater activity where positional iso-
mers were possible. The nature of the opposite ‘ortho’
position clearly had a bearing on activity in line with
QSAR predictions. Thus, the pyrazole 23 presenting a
nitrogen at this position was much less active than imid-
azole 18, which in turn was possibly eclipsed in activity
by the 1H-imidazol-5-yl isomer 22, which would have
higher C–H acidity. However, this isomer was not pur-
sued further as it was synthetically much less tractable12
and carried a greater P450 binding interaction risk as it
lacked a 2-substituent on the imidazole ring. The isoxaz-
ole analogue 24 (Table 3) was also a potent fXa inhibi-
tor albeit with poorer plasma-based activity.
Compound t1/2 (h) Clpb (ml/min/kg) Vssc (L/kg) Fd (%)
a
13
14
15
0.8
1.0
0.8
18
13
39
0.7
0.6
1.1
16
52
10
a t1/2, half-life of the test compound expressed in hours.
b Clp, plasma clearance of the test compound expressed as mL/min/kg.
c Vss, steady state volume of distribution of test compound expressed
as L/kg.
d F, oral bioavailability of test compound expressed as percentage.
fXa inhibitors with substantially improved anticoagu-
lant activities compared with compounds described in
our accompanying paper.2 Pharmacokinetic parameters
for these analogues were determined in the rat (Table
3)13 and the profile for the (5-chlorothien-2-yl)ethenyl
analogue 14 was particularly attractive as it maintained
the highly encouraging profile reported for closely
related non-basic analogues,2 including good oral
bioavailability.
Thus, within the preferred 2-(dimethylamino)methyl-
1H- imidazol-1-yl series, the 5-chlorothienyl-based ana-
logues 13, 14 and 15 (Table 1) were identified as potent

32
R. J. Young et al. / Bioorg. Med. Chem. Lett. 18 (2008) 28–33
Table 4. fXa inhibitory activities,8 anticoagulant potency9 and measured hydrophobicity11a/human serum albumin binding11b and measured/
calculated pKa data15 for compounds 14 and 29 to 34
H
N
N
F
O
S
O
O
N
S
Cl
N
R2
N
R3
R2
R3
fXa Ki (nM)
1.5· PT (lM)
CHI LogD7.4
Meas. pKa
Calc. pKa ACD v8.0
%HSA bound
15
Entry
29
30
31
32
33
Morpholine
Pyrrolidine
1.2
0.4
10.9
2.1
2.28
2.21
2.7
5.75
7.95
—
5.8
87.9
92.0
95.8
93.8
94.0
8.86
8.0
Me
Me
i-Pr
Et
0.6
0.4
4.4
3.4
2.48
2.58
—
—
7.92
6.53
3-Fluoro
pyrrolidine
16.4
14.5
34
14
Me
Me
H
Me
<1
0.2
3.7
4.2
1.7
2.69
—
7.26
8.55
7.84
88.6
92.1
Table 5. fXa inhibitory activities,8 for individual enantiomers 35 and
36 of compound 14
Whist exploring topology in the previous sets, the nature
of the distal ring of the P4 ring was clearly having an ef-
fect on both the intrinsic hydrophobicity (that of the un-
charged species, i.e. logP) and pKa of the molecules.
Thus having now identified 1H-imidazol-1-yl as our
optimum distal ring we next evaluated a set of amine
substituents that, in particular, allowed us to further ex-
plore the impact of modulating hydrophobicity through
pKa changes and its impact on structure property rela-
tionships (Table 4).14
H
H
N
N
F
N
N
O
S
O
O
O
N
S
Cl
N
(S)-36
(R
)-35
Me2N
Entry
Stereochemistry
fXa Ki (nM)
14
35
36
RS
0.2
5
Through these changes a number of compounds were se-
cured that displayed good plasma-based activity. How-
ever, the measured hydrophobicity values were in a
relatively narrow range and any trends were not clear
cut. The overall profiles did not offer any significant advan-
tage over the dimethylamino derivative 14 (Table 4).
(R)-
(S)-
<1
The preferred absolute stereochemistry in the promising
analogue 14 was established through a combination of
approaches. Chiral preparative hplc16 furnished the indi-
vidual enantiomers 35 and 36; both isomers were potent
fXa inhibitors with 36 showing significantly greater
activity (Table 5). The absolute stereochemistry of 36
was established as the (3S)-isomer through asymmetric
synthesis (via intermediate 9, Scheme 1) with further sup-
port from an X-ray crystal structure of (3S)-36 bound
into factor Xa (Fig. 1).17 This corroborated the antici-
pated binding modes, whereby the imidazole 5-proton
was located near to the Trp215 residue and the pendant
dimethylamino group was located close to the carbonyl
oxygen of Glu97, although the electron density was such
that this position was not unequivocally defined. This
latter observation was perhaps consistent with there
being no significant potency increase that may have been
attributed to such a hydrogen bonding interaction.
In summary, this work, based on structure and property
based design, has led to the identification of a series of
aminopyrrolidin-2-one-based fXa inhibitors with biaryl
P4 motifs and basic substituents. Through optimising
the nature and connectivity of the distal ring and substi-
tuent, (3S)-36 in particular was identified as a highly
Figure 1. X-ray crystal structure of 36 bound into fXa, showing S4
interactions as described in the text, highlighting the proximity of the
ortho hydrogen to an enriched area of electron density on Trp215 and
the likely position of the diamino side chain close to the carbonyl of
Glu97.

R. J. Young et al. / Bioorg. Med. Chem. Lett. 18 (2008) 28–33
33
potent and selective18 fXa inhibitor with significant plas-
ma-based activity and an encouraging oral pharmacoki-
netic profile.19 These findings provided the impetus for
further studies on the refinement of this template which
will be reported in due course.
(d) Jia, Z. J.; Wu, Y.; Huang, W.; Zhang, P.; Clizbe, L. A.;
Goldman, E. A.; Sinha, U.; Arfsten, A. E.; Edwards, S. T.;
Alphonso, M.; Hutchaleelaha, A.; Scarborough, R. M.;
Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2004, 14, 1221.
6. (a) Oi, R.; Shimakawa, C.; Takenaka, S. Chem. Lett. 1988,
5, 899; (b) Zhou, J. C; Confalone, P. N.; Li, H.-Y.; Oh, L.
M.; Rossano, L. T.; Clark, C. G.; Teleha, C. A. WO
008199 A2, 2002.
7. (a) Sakamoto, T.; Uchiyama, D.; Kondo, Y.; Yamanaka,
H. Chem. Pharm. Bull. 1993, 41, 478; (b) Uchiyama, D.;
Yabe, M.; Kameyama, H.; Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1996, 43, 1301.
8. Factor Xa inhibitory activities were determined using
Rhodamine 110, bis-(CBZ-glycylglycyl-L-arginine) amide
as fluorogenic substrate; details are described in Ref. 3b.
9. Anticoagulant activities were determined in the prothrom-
bin time (PT) assay; see Ref. 3b.
Acknowledgments
We thank Alan Hill, Pat McDonough, Shenaz Nunhuck
´
and Klara Valko for constructive discussions and per-
forming the physical measurements reported.
´
References and notes
10. Young, R. J.; Brown, D.; Burns-Kurtis, C. L.; Chan, C.;
Convery, M. A.; Hubbard, J. A.; Kelly, H. A.;Pateman, A. J.;
Patikis, A.; Senger, S.; Shah, G. P.; Tooomey, J. R.; Watson,
N. S.; Zhou, P. Bioorg. Med. Chem. Lett. 2007, 17, 2927.
11. Hydrophobicity measurements are reported as Chromato-
graphic Hydrophobicity Index (CHI) logD7.4 values, for
1. (a) Quan, M. L.; Smallheer, J. M. Curr. Opin. Drug
Discov. Dev. 2004, 7, 460; (b) Gould, W. R.; Leadley, R.
J. Curr. Pharm. Des. 2003, 9, 2337; (c) Hirsh, J.;
O’Donell, M.; Weitz, J. I. Blood 2005, 105, 453; (d)
Golino, P.; Loffredo, F.; Riegler, L.; Renzullo, E.;
Cocchia, R. Curr. Opin. Invest. Drugs 2005, 6, 298; (e)
Alexander, J. H.; Singh, K. P. Am. J. Cardiovasc. Drugs
2005, 5, 279; (f) McBride, B. F. J. Clin. Pharmacol.
2005, 45, 1004.
2. Young, R. J.; Borthwick, A. D.; Brown, D.; Burns-Kurtis,
C. L.; Campbell, M.; Chan, C.; Charbaut, M.; Chung,
C.-W.; Convery, M. A.; Kelly, H. A.; King, N. P.;
Kleanthous, S.; Mason, A. M.; Pateman, A. J.; Patakis, A.
N.; Pinto, I. L.; Pollard, D. R.; Senger, S.; Shah, G. P.;
Toomey, J. R.; Watson, N. S.; Weston, H. E. Bioorg. Med.
Chem. Lett. 2007, preceding paper.
´
details see (a) Valko, K.; Du, C. M.; Bevan, C.; Reynolds,
D. P.; Abraham, M. H. Curr. Med. Chem. 2001, 8, 1137;
High throughput human serum albumin binding was
´
measured as described in (b) Valko, K.; Numhuck, S.;
Bevan, C.; Abraham, M. H.; Reynolds, D. P. J. Pharm.
Sci. 2003, 92, 2236.
12. In the Ullmann coupling the ratio of the desired 1H-
imidazol-5-yl (which led to 22) to the ultimately less active
1H-imidazol-4-yl (e.g., 25) was ca. 1:3, an outcome
compounded by minimal chromatographic separation of
the isomeric compounds.
13. The formulation used for both iv and po dosing was a
5:95% (v/v) mixture of DMSO and 50:50 PEG-200:ster-
ile water. Serial blood samples were collected into
heparinised containers at various time-points and blood
3. (a) Watson, N. S.; Brown, D.; Campbell, M.; Chan, C.;
Chaudry, L.; Convery, M. A.; Fenwick, R.; Hamblin, J.
N.; Haslam, C.; Kelly, H. A.; King, N. P.; Kurtis, C.
L.; Leach, A. R.; Manchee, G. R.; Mason, A. M.;
Mitchell, C.; Patel, C.; Patel, V. K.; Senger, S.; Shah, G.
P.; Weston, H. E.; Whitworth, C.; Young, R. J. Bioorg.
Med. Chem. Lett. 2006, 16, 3784; (b) Chan, C.;
Borthwick, A. D.; Brown, D.; Campbell, M.; Chaudry,
L.; Chung, C.-W.; Convery, M. A.; Hamblin, J. N.;
Johnstone, L.; Kelly, H. A.; Kleanthous, S.; Kurtis, C.
L.; Patikis, A.; Patel, C.; Pateman, A. J.; Senger, S.;
Shah, G. P.; Toomey, J. R.; Watson, N. S.; Weston, H.
E.; Whitworth, C.; Young, R. J.; Zhou, P. J. Med.
Chem. 2007, 50, 1546.
4. Young, R. J.; Campbell, M.; Borthwick, A. D.; Brown,
D.; Burns-Kurtis, C. L.; Chan, C.; Convery, M. A.;
Crowe, M. C.; Dayal, S.; Diallo, H.; Kelly, H. A.; King,
N. P.; Kleanthous, S.; Mason, A. M.; Mordaunt, J. E.;
Patel, C.; Pateman, A. J.; Senger, S.; Shah, G. P.; Smith,
P. W.; Watson, N. S.; Weston, H. E.; Zhou, P. Bioorg.
Med. Chem. Lett. 2006, 16, 5953.
centrifuged to yield plasma. These studies used
animals for each (iv/po) leg.
2
14. The impact of varying analogous substituents on param-
eters including protein binding and permeation was
discussed in Ref. 5a–c, whilst pH-related issues affecting
the absorption of Razaxaban were noted in a recent
disclosure; Farag Badawy, S. I.; Gray, D. B.; Zhao, F.;
Sun, D.; Schuster, A. E.; Hussain, M. A. Pharm. Res.
2006, 23, 989.
15. Spectroscopic pKa measurements were performed on a
Sirius GLpKa D-PAS instrument and predicted pKa values
were calculated using Advanced Chemistry Development
software v8.0.
16. The enantiomers were separated on a Chiracel AS volume,
eluted with 60% ethanol in heptane, with analytical
retention times of 4.9 minutes (3R)-35 and 7.1 min (3S)-
36; this was scaled for preparative separations, which
furnished individual compounds with >98% ee.
5. Basic biaryl P4 motifs in other series of fXa inhibitors
have been reported, for example (a) Pinto, D. J. P.;
Galemmo, R. A.; Quan, M. L.; Orwat, M. J.; Clark, C.;
Li, R.; Wells, B.; Woerner, F.; Alexander, R. S.; Rossi, K.
A.; Smallwood, A.; Wong, P. C.; Luettgen, J. M.;
Rendina, A. R.; Knabb, R. M.; He, K.; Wexler, R. R.;
Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2006, 16, 5584; (b)
Quan, M. L.; Han, Q.; Fevig, J. M.; Lam, P. Y. S.; Bai, S.;
Knabb, R. M.; Luettgen, J. M.; Wong, P. C.; Wexler, R.
R. Bioorg. Med. Chem. Lett. 2006, 16, 1795; (c) Quan, M.
L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li,
R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.;
Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.;
Wong, P. C.; Wexler, R. R. J. Med. Chem. 2005, 48, 1729;
17. The crystal was soaked with the single enantiomer 36.
Electron density for the dimethylaminomethyl portion of
the molecules was very poor, the only significant density
being at the position where the amino group is modelled.
˚
The structure for 36 was refined at 1.7 A (overall Rmerge is
0.073) in Refmac5 to a final Rfactor of 0.189 and Rfree of
0.215, using procedures described in Ref. 3b. Co-ordinates
are deposited in the protein data bank with code 2vh0.
18. Compound 36 was at least >100-fold selective against a
panel of trypsin-like serine proteases; indeed such levels of
selectivity were observed across this series.
19. The pharmacokinetic profiles of the individual enantiomers
35 and 36 were closely similar to that of the racemate 14.