Structure-based design and synthesis of macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.01.036

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.

Full text of DOI:10.1016/j.bmcl.2009.01.036

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1361–1365
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design and synthesis of macrocyclic peptidomimetic
b-secretase (BACE-1) inhibitors
*
Rainer Machauer , Siem Veenstra, Jean-Michel Rondeau, Marina Tintelnot-Blomley,
Claudia Betschart, Ulf Neumann, Paolo Paganetti
Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide
inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design
and syntheses of a series of macrocyclic analogues 3a–h covalently linking the P1 and P3 side-chains.
These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also
shows activity in a cellular system.
Received 24 November 2008
Revised 9 January 2009
Accepted 14 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
BACE-1 inhibition
Macrocyclization
Hydroxyethylene transition-state mimetic
Alzheimer’s disease (AD) is a devastating neuro-degenerative
disorder characterized by progressive cognitive decline. At severe
stages of the disease, AD patients cannot manage daily life and de-
pend completely on caregivers. Since its description by Alois Alz-
heimer in 1907, the prevalence of AD is steadily increasing,
mostly because of the growing aged population.1 In spite of the ris-
ing demand for medication, no truly disease-modifying therapies
are yet available. AD is characterized histopathologically by the
occurrence of amyloid plaques and neurofibrillar tangles in the
brain.2 Three key findings underpin the current drug discovery ef-
forts towards a therapy for AD: The detection of b-amyloid pep-
tides (Ab40/42) as the main components of amyloid plaques,3 the
identification of the amyloid precursor protein (APP),4 and the dis-
covery of autosomal dominant mutations in the APP gene linked to
early-onset AD.5 The b-amyloid hypothesis is now widely accepted
as the central paradigm in the pathogenesis of AD.6 According to
this model, aggregated b-amyloid peptides with 40 or 42 residues
in length (Ab40/42) are neurotoxic and initiate a cascade of events
leading to neuronal degeneration. Ab40/42 generation from APP re-
quires two consecutive endoproteolytic cleavages. In a first step,
APP is cleaved by BACE-1 (b-site APP cleaving enzyme), a mem-
brane-bound aspartyl protease.7
is widely considered an attractive therapeutic approach for the
treatment and prevention of AD.8
Besides other hit finding activities, such as high throughput
screening of large compound libraries using biochemical or binding
assays, the sequence of the natural substrate protein is a classical
starting point for a structure-based approach to protease inhibi-
tion. From past medicinal chemistry efforts to design inhibitors
of renin and HIV protease, effective strategies to convert sub-
strate-based peptidomimetics into drug-like inhibitors are well
documented.9 However, endoproteases typically make use of sev-
eral binding interactions along the substrate backbone within the
active-site cleft to achieve low nanomolar binding affinities. This
explains why their inhibitors often have a relatively high molecular
weight (500 Da and above), triggering considerable subsequent ef-
forts to optimize their pharmacokinetic properties. Large pepti-
domimetic inhibitors usually do not enter the brain due to their
unfavorable physicochemical profile (high polar surface area and
high number of H-bond donors and acceptors). While this is less
of an issue for targets exclusively located in the periphery (e.g.,
renin), other indications require at least some degree of brain pen-
etration (e.g., HIV protease). From this perspective, the structure-
based design of a brain-penetrating BACE-1 inhibitor undoubtedly
represents an extreme case and a formidable challenge. Having all
the above mentioned issues in mind but confronted with a limited
number of hits from high-through-put screenings we decided to
test whether the substrate sequence can be reduced to a peptidic
inhibitor of reasonable size and potency. If this proves feasible
we thought further improvements of the pharmacokinetic and
CNS penetration properties by reducing the number of rotatable
The resulting membrane-tethered C99 fragment is further pro-
cessed by c-secretase releasing the neurotoxic Ab40 or Ab42. Since
BACE-1 knock-out/APPtransgenic mice are viable, but lack com-
pletely Ab40/42 and do not form amyloid plaques, BACE-1 inhibition
* Corresponding author. Tel.: +41 61 6963431; fax: +41 61 6962455.
E-mail address: rainer.machauer@novartis.com (R. Machauer).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.036

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R. Machauer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1361–1365
P4
P3
P2
P1
P1'
P2'
P3'
P4'
O
O
O
O
H
N
H
N
H2N
OH
N
H
N
H
N
H
N
H
O
OH
O
O
O
OM99-2
H2N
HO
O
HO
O
O
O
H
N
N
H
N
H
O
OH
1
S
Figure 2. Cocrystal structure of 1 in complex with BACE-1. The BACE-1 active-site is
shown in surface representation. For clarity the flap residues 69–75 (shown in gray
sticks) were omitted from the surface calculation. 1 is shown in thick ball-and-stick
with yellow carbon atoms. An overlay with OM99-2 is shown in thin ball-and-stick
with green carbon atoms.
R1
N
O
O
N
H
N
H
O
OH
2a
2b
R1 = H
R1 = Me
drastic reduction in size was partly compensated by more exten-
sive hydrophobic interactions contributed by the C-terminal
n-butylamino group in the S20 subsite, and by the N-terminal
4-methyl-pentanoic group occupying the S3 pocket. More impor-
tantly, the X-ray analysis showed that this amino-terminal alkyl
group was in van der Waals contact (3.8 Å) to the P1 isobutyl group
filling the neighboring S1 pocket, without any intervening enzyme
residue. With the two alkyl side-chains in such close vicinity, the
concept of bridging P1 and P3 was very appealing. Furthermore,
the nearest protein residues (Leu30, Ile110, Trp115) were at a dis-
tance of about 4 Å, with the S1 and S3 subsites forming a continu-
ous pocket lined by hydrophobic residues (Tyr71, Ile118, Phe108,
Leu30, Trp115, Ile110). The topology of the BACE-1 active-site
was thus found to be fully compatible with the introduction of a
linker connecting P1 and P3.
R2
R1
N
O
O
n
N
H
N
H
O
OH
3a-h
Figure 1. Peptide inhibitor OM99-2 and peptidic lead structures 1, 2a/b and
macrocyclic inhibitors 3a–h of BACE-1.
bonds,10 PSA, etc. should be possible as for HIV protease and could
be addressed in next design cycles.
The macrocyclization strategy was also supported by the suc-
cess of this approach as an established method to pre-organize
and stabilize bioactive conformations, especially tripeptide b-
strands.15 Its effectiveness has already been demonstrated for
other aspartic proteases, and we were hoping to earn at least some
of its expected benefits in terms of improved enzymatic potency,
cellular activity/permeability and proteolytic stability.16 During
the course of our project other groups also published on related ap-
proaches for BACE-1 inhibitors.17
For our approach we started from OM99-2, using the first X-ray
crystallography data of a ligand – BACE-1 complex published by
Tang and collaborators.11 This substrate-derived octapeptide
inhibitor with nanomolar potency Ki = 1.6 nM (OM99-2, Fig. 1) is
spanning the P4–P40 subsites. In order to define a minimal core
of binding interactions, we first aimed at reducing the size of
OM99-2 while preserving low micromolar activity. This effort re-
sulted in compound 1, a three residue hydroxyethylene transi-
tion-state inhibitor, exhibiting 1.4 lM potency in the BACE-1
Molecular modeling – docking studies using QXP/mcdock in the
Flo modeling package18 – indicated the use of a two- or three-carbon
linker to connect the P1 and P3 side-chains. As suggested by the P1/
P3 distance in the bound conformation of 1, a 14-membered macro-
cycle was calculated to bring the P1 and P3 alkyl chains too close
together thus resulting in suboptimal occupation of the S3 pocket.
The 15-membered ring was predicted to improve S3 filling, but a
solvent accessible surface representation showed that the fit was
not yet optimal. Thus, enlarging the ring by one further carbon to a
16-membered ring appeared to preserve optimally the relaxed con-
formation of P1 and P3 while achieving the best fit with regard to
Leu30 and Trp115. In contrast, the 17-membered ring was predicted
to be too bulky for the pocket forcing the macrocycle into a confor-
mation which would be energetically less favorable and clearly less
tightly fitting. The model of the 15- or 16-membered macrocycles
favored in QXP docking calculations are shown in Figure 3.
enzymatic assay but only 12% inhibition at 10
lM in a cellular
system.12
According to published subsite specificities for BACE-1, the
methionine side-chain was not expected to contribute significantly
to binding in S2.13 Its reduction to alanine was possible without
major loss of activity, leading to compound 2a with an activity of
3.7 lM in the enzymatic assay. Inspection of the X-ray structure
of the OM99-2 – BACE-1 complex showed the absence of hydrogen
bonded interactions between the P2/P3 amide nitrogen and the
protein. We therefore prepared the N-methyl-alanine analogue
2b. This more rigid open-chain inhibitor displayed enzymatic
activity (2.4 lM) and cellular potency comparable to 1.
The co-crystal structure of BACE-1 in complex with 1 was deter-
mined at 2.0 Å resolution.14 The crystallographic data showed that
the key binding interactions observed in the OM99-2 complex, in
particular those involving the transition-state mimetic and the
three backbone amide bonds, were conserved in the complex with
inhibitor 1 (Fig. 2). The loss of binding energy resulting from the
Furthermore, modeling suggested the conservation of the
resulting methyl group in P1 with (R)-stereochemistry, while the

R. Machauer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1361–1365
1363
dipeptide isosteres. The acyl-imminium equivalents 6a and b were
accessible from (R)-citronellal (7a) and pent-4-enal (7b) by a stan-
dard condensation procedure.19
To prepare the macrocyclic inhibitors 3a–h we started with the
condensation of the aldehydes 7a and b with sodium toluenesulf-
inate and tert-butyl-oxycarbonyl amine in the presence of formic
acid, followed by the alkylation of the sulfinates with lithiated
2,5-dihydro-2-furanone (Scheme 2). The diastereomeric mixture
of (R)-citronellal derived (R,R)- and (S,S)-butenolide 5a was sub-
jected to hydrogenation and ozonolysis to provide aldehyde 8. Wit-
tig reaction and alkylation afforded a diastereomeric mixture of
lactone 9a. The conversion of the triple substituted double bond
into a terminal double bond was necessary since metathesis reac-
tions with the triple substituted double bond were not successful.
In case of the achiral aldehyde 7b the butenolide 5b was hydroge-
nated and methylated to provide 9b. After amine deprotection and
coupling with Boc-alanine or Boc-N-methyl-alanine the two dia-
stereomers were separated by chromatography. Subsequent cleav-
age of the Boc group provided the central intermediates 10a–c.
Various acids were coupled and ring-closing metatheses with
Grubbs second generation catalyst afforded the macrocyclic olefins
11a–h.20 Opening of the d-lactones with n-butylamine followed by
hydrogenation provided the inhibitors 3a–h.
Figure 3. Examples for 15-membered (red) and 16-membered (blue) macrocycles
as modeled in the X-ray structure of 1 (green).
resulting methyl group in P3 – in the model close to the Gln12/
Gly13 amide – was deemed less crucial. In order to explore the
validity of this approach, the macrocyclic analogues 3a–h (Fig. 1)
of compounds 2a and b were synthesized.
As outlined in Scheme 1 we prepared the macrocyclic inhibitors
3a–h by ring-closing metathesis (RCM) followed by aminolysis of
the d-lactone and hydrogenation. The cyclization precursors 4a–h
were obtained from the dipeptide isostere precursors 5a and b
by hydrogenation of the internal double bond, diastereo-selective
alkylation and standard coupling and deprotection steps, followed
by separation of the two diastereomers. (In case of 5a the triple
substituted double bond was also converted into a terminal double
bond.)
The unsaturated d-lactones 5a and b were synthesized by addi-
tion of lithiated 5H-furan-2-one into the corresponding amido-
sulfones 6a and b. We applied this approach since we had observed
in preceding exploratory experiments that this addition gave selec-
tively access to the two trans (threo) isomers of the four possible
addition products (unpublished results). This reaction and its
selectivity for which we did not find any literature precedence thus
represent a new method for the synthesis of hydroxyethylene
R3
R3
R2
R3
R2
a, b
CHO
m
R3
m
O
R2, R3 = H,
m = 0
c and f
O
N
H
7a,b
R2, R3 = Me,
m = 1
c, d
O
5a,b
O
O
R2
m
O
O
e, f
O
N
O
N
H
H
O
O
9a,b
O
O
8
R2
R2
R2
R2
R1
N
O
O
m
R1
N
m
n
O
R1
H2N+
Cl
O
n
m
i, j
R1
N
g, h
O
N
H
N
H
n
N
H
O
N
H
OH
N
H
O
O
O
O
O
O
3a-h
4a-h
O
10a-c
O
11a-h
R
R
R2
O
O
*
*
R1
N
O
k, l
O
N
H
S
O
O
O
N
H
n
O
O
N
N
H
O
H
6a,b
5a,b
O
OH
3a-h
Scheme 2. Reagents and conditions: (a) Sodium toluenesulfinate, BocNH2, formic
acid; (b) 5H-furan-2-one, LHMDS, ꢀ70 °C to ꢀ50 °C, 81% for two steps; (c) H2,
Raney-Ni; (d) ozone, PPh3, 92% for two steps; (e) Ph3PCHþ3 Brꢀ, KOtBu, ꢀ40 °C; (f)
LHMDS, DMPU, MeI, ꢀ78 °C, 69% for two steps; (g) 4N HCl in dioxane; (h) Boc-
AA-OH, HOBt, EDC, Et3N, 74% for two steps, separation of 2 diastereomers; (i) 4N
HCl in dioxane, 99%; alkenyl acid, HOBt, EDC, Et3N; (j) Grubbs 2nd generation
catalyst, 40 °C, 75% for two steps; (k) n-butylamine, 50 °C, (l) H2, Pd-C, 99% for
two steps.
CHO
CHO
7a
7b
Scheme 1. Retrosynthetic analysis of compounds 3a–h.

1364
R. Machauer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1361–1365
Table 1
Enzymatic and cellular inhibition assay results for compounds 1, 2a and b and 3a–h
R2
R1
O
O
n
N
N
H
N
H
O
OH
3a-h
Compound
R1
R2
n
BACE-1 inhibition IC50
,
l
Ma
Cellular inhibition % at 10
l
Ma
hCathD inhibition IC50
0.37
, l
Ma
1
H
H
Me
H
H
H
H
H
H
–
–
–
Me
Me
H
Me
H
–
–
–
0
1
1
2
2
3
1
1.4
3.7
12
2a
2b
3a
3b
3c
3d
3e
3f
7*
31% at 10
34% at 10
n.a.
l
l
M
M
2.4
10*
n.a.
16*
8*
1.6*
0.59
7.6
46% at 10
18% at 10
1.7
l
l
M
M
0.25
27*
n.a.
15**
17*
46% at 10
l
M**
n.a.
n.a.
Me
Me
2.1*
3g
Me
2.5
16% at 10
lM
3h
Me
Me
2
0.15
60
8.1
IC50 values for BACE-1 and cathepsin D inhibition, and inhibition of cellular release of Ab40 were determined as described.12
a
Values are means of at least three experiments (n.a., not available).
*
Two measurements.
Single measurement.
**
The binding data for the macrocycles 3a–h were in good agree-
ment with the predictions. The 14-membered macrocycle 3a
showed an activity of 1.6 lM in the enzymatic assay, which is only
volved in hydrophobic contacts to Leu30 (3.5 Å), Ile110 (3.8 Å)
and Trp115 (4.0 Å). These interactions appeared to stabilize a dif-
ferent conformer of the Ile110 side-chain.
a 2-fold increase in activity over 2a (Table 1). Expanding the mac-
rocyclic core by one methylene unit to the 15-membered ring 3b,
In line with the prediction, further ring-expansion to the 16-
membered macrocycle 3d proved to be optimal resulting in a po-
did indeed increase the activity to 0.59
lM. The 6-fold improve-
tency of 0.25 lM in the enzymatic assay corresponding to a 15-fold
ment over compound 2a was ascribed to a better stabilization of
the bioactive conformation. But the increase in potency in the
enzymatic assay was only partly reflected in the cellular activity
improvement over 2a. The critical importance of the P1 methyl
group is demonstrated by the inhibitors 3c and 3e which lack this
group and show a significant loss in activity compared to 3b and
3d. The cellular potencies of the inhibitors 3b–h were also lower
in comparison to the enzymatic activities by more than one order
of magnitude. The peptidic character of the inhibitors 3a–f was
suspected to be responsible for the discrepancy between the enzy-
matic and the cellular potency, since these compounds encom-
passed three amide bonds. To test this hypothesis we removed
the H-bond donor by N-methylation of the P2–P3 amide which
does not contribute to BACE binding leading to macrocycles 3g
and h. Again in line with modeling predictions for the 15-mem-
bered analogue 3g a slightly (4-fold) reduced potency in the enzy-
matic assay compared to 3b was observed. While in the case of the
16-membered ring the P2/3N-methylated macrocycle fitted tightly
and weakly improved (2-fold) the enzymatic activity over 3d, to
(16% reduction of Ab1ꢀ40 release at 10 lM), which was only im-
proved 2-fold over the matching open-chain analogue 2a.
Crystallographic analysis at 2.1 Å resolution of the BACE-1 com-
plex with 3b fully confirmed the modeling predictions regarding
the binding mode of the inhibitor, and the conformation of ac-
tive-site residues (Figure 4).
As shown in Figure 4, the cyclization had hardly any effect on
the binding of the P1 and P2 groups, while the position of the
hydroxyethylene transition-state mimic and the P’ groups were
not affected at all by this modification. The alkyl linker was in-
0.15 lM for 3h. The removal of the H-bond donor of the P2–P3
amide in the macrocycles 3g and h, involving the replacement of
one water molecule present in the X-ray, had no significant nega-
tive impact on their potency, similar to the open-chain analogues
2a and b, but seemed to influence the preferred ring size. However,
methylation of the P2-P3 amide in 3g and h did not improve the
potency in the cellular assay to an extent as seen in the enzymatic
assay. For the most potent macrocycle 3h the cellular activity of 8.7
(
0.9) lM remained 1–2 orders of magnitude lower than that
determined in the enzymatic assay.
In parallel to the BACE-1 activity we also monitored the inhibi-
tion of human cathepsin D (CathD), a related aspartyl protease in-
volved in lysosomal protein degradation and cancer.21 The peptidic
lead structure 1 was 4-fold selective over CathD. Macrocyclization,
different ring-sizes, and N-methylation of the P2–P3 amide im-
proved BACE-1 selectivity over CathD. Compound 3d displayed 6-
fold selectivity, whereas the selectivity over CathD increased to
56-fold for the most potent BACE-1 inhibitor 3h.
Figure 4. Overlay, based on protein C
inhibitors 1 (yellow/gray carbon atoms) and 3b (green carbon atoms).
a atoms, of the BACE-1 complexes with

R. Machauer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1361–1365
1365
8. Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B. D.; Babu-Khan, S.; Denis, P.; Fan, W.; Kha,
H.; Zhang, J.; Gong, Y.; Martin, L.; Louis, J.-C.; Yan, Q.; Richards, W. G.; Citron,
M.; Vassar, R. Nat. Neurosci. 2001, 4, 231.
9. (a) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueeger, H.; Göschke, R.; Cohen, N.
C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grütter, M. G. Chem. Biol.
2000, 7, 493; (b) Wood, J. M.; Maibaum, J.; Rahuel, J.; Grütter, M. G.;
Cohen, N. C.; Rasetti, V.; Rueeger, H.; Göschke, R.; Stutz, S.; Fuhrer, W.
Biochem. Biophys. Res. Commun. 2003, 308, 698; (c) Tomasselli, A. G.;
Heinrikson, R. L. Biochim. Biophys. Acta (BBA) – Protein Struct. Mol. Enzymol.
2000, 1477(1–2), 189.
10. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D.
J. Med. Chem. 2002, 45, 2615.
11. (a) Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, s.; Gosh, A. K.; Zhang, X. C.;
Tang, J. Science 2000, 290, 150; (b) Ghosh, A. K.; Bilcer, G.; Harwood, C.;
Kawahama, R.; Shin, D.; Hussain, K. A.; Hong, L.; Loy, J. A.; Nguyen, C.; Koelsch,
G.; Ermolieff, J.; Tang, J. J. Med. Chem. 2001, 44, 2865.
In summary, we report the structure-based design of novel P1–
P3 linked macrocyclic BACE-1 inhibitors based on crystallographic
data obtained for the open-chain compound 1. In agreement with
modeling studies, the 15- and 16-membered macrocycles 3b and
3d were more active compared to their open-chain analogues 2a
and b, without increasing their molecular weight. The binding
mode of 3b to BACE-1 was confirmed by crystallographic analysis.
Sufficient occupancy of P1 by methyl substitution of the alkyl chain
appeared necessary to reach submicromolar BACE-1 inhibition.
The macrocyclization alone did not improve cellular potency.
Notably, the reduction of the peptidic character of the macrocyclic
inhibitors by methylation of the P2/3 amide retained the enzy-
matic activity but did not improve the cellular activity to the same
level. The macrocyclic inhibitors proved also to be weakly to mod-
erately selective over the related aspartyl protease CathD.
12. (a) Hannesian, S.; Yun, H.; Hou, Y.; Yang, G.; Bayrakdarian, M.; Therrien, E.;
Moitessier, N.; Roggo, S.; Veenstra, S.; Tintelnot-Blomley, M.; Rondeau, J.-M.;
Ostermeier, C.; Strauss, A.; Ramage, P.; Paganetti, P.; Neumann, U.; Betschart, C.
J. Med. Chem. 2005, 48, 5175; (b) The cellular activity was determined in
Chinese Hamster Ovary cells, stably transfected with human wild-type APP.
Acknowledgments
Compounds (0.003–10 lM) were incubated with adherent cells in 96 well
plates (n = 3 for each concentration) for 24 h. Supernatant concentration of
amyloid peptide 1–40 was analyzed using Europium-labeled beta-1 (N-
terminus) and XL-665 labeled 25H10 (C-terminus) in-house antibody and
homogenous time resolved fluorescence detection on a PHERAstar instrument
(BMG Labtech, Offenburg, Germany). Cell viability was determined using MTT
staining.
For the BACE complex with 3b, X-ray data collection was per-
formed at the Swiss Light Source, Paul Scherrer Institut, Villigen,
Switzerland. We are grateful to the machine and beamline groups
whose outstanding efforts have made this experiment possible.
We thank C. McCarthy for proofreading the manuscript.
13. Turner, R. T., III; Koelsch, G.; Hong, L.; Castanheira, P.; Gosh, A.; Tang, J.
Biochemistry 2001, 40, 10001.
14. X-ray coordinates for the complex of BACE with inhibitors 1 and 3b have been
deposited in the Protein Data Bank (http://www.rcsb.org), and can be accessed
under PDB ID: 3DUY and 3DV1.
Supplementary data
15. Reid, R. C.; Kelso, M. J.; Scanlon, M. J.; Fairlie, D. P. J. Am. Chem. Soc. 2002, 124,
5673.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.01.036.
16. (a) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nature Rev. Drug Disc. 2008, 7,
608; (b) Tyndall, J. D. A.; Reid, R. C.; Tyssen, D. P.; Jardine, D. K.; Todd, B.;
Passmore, M.; March, D. R.; Pattenden, L. K.; Bergman, D. A.; Alewood, D.; Hu,
S.-H.; Alewood, P. F.; Birch, C. J.; Martin, J. L.; Fairlie, D. P. J. Med. Chem. 2000,
3495, 43.
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