Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2009.06.020

Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFκB agonist activity was optimised in an iterative process from pIC₅₀ 7.5 (for 7), to pIC₅₀ 10.1 (for 38E1). An explanation for the SAR observed base

Full text of DOI:10.1016/j.bmcl.2009.06.020

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4846–4850
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists
Keith Biggadike, Matilde Caivano, Margaret Clackers, Diane M. Coe, George W. Hardy, Davina Humphreys,
Haydn T. Jones, David House, Annette Miles-Williams, Philip A. Skone, Iain Uings, Vicki Weller,
*
Iain M. McLay, Simon J. F. Macdonald
Medicines Research Centre, Respiratory CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFjB agonist activity
Received 14 April 2009
Revised 3 June 2009
Accepted 5 June 2009
Available online 13 June 2009
was optimised in an iterative process from pIC50 7.5 (for 7), to pIC50 10.1 (for 38E1). An explanation
for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of
the glucocorticoid receptor.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glucocorticoid
Agonist
Non-steroidal
Tractable
Glucocorticoid receptor (GR) agonists have been used for many
years as anti-inflammatory agents for treating a whole spectrum of
conditions including asthma and rheumatoid arthritis.1 Whilst ste-
roids such as prednisolone and dexamethasone are used orally, flu-
ticasone propionate 1 is commonly used in the clinic as an inhaled
treatment for asthma and rhinitis.2 Fluticasone furoate (VeramystÒ
or AvamysÒ) 2 is a new GR agonist approved by the FDA in 2007 for
the once daily intranasal therapy for seasonal allergic rhinitis.3 Flu-
ticasone propionate sales for intranasal and inhaled treatments in
2007 totalled over £800 million.4 Fluticasone propionate is also a
component of AdvairÒ (or SeretideÒ) as an inhaled treatment for
asthma and chronic obstructive pulmonary disease sales of which
totalled £3.4 billion in 2007.4 Recent reports for new inhaled corti-
costeroids (steroidal in structure) include ciclesonide (approved by
the FDA in 2008 and marketed as AlvescoÒ),5 androstadiene C-17
esters from Sandham at Novartis6 and other androstene derivatives
from GSK,7 but the principle research focus has been the search for
non-steroidal GR agonists which maintain anti-inflammatory
activity whilst having reduced side effects.8
similar potency could be developed with non-steroidal structures.
Such compounds might form the basis for future inhaled or intra-
nasal therapies for respiratory disease. We describe here a series of
compounds with sub-nanomolar potency which, as far as we are
aware, are among the most potent non-steroidal agonists de-
scribed in the literature so far.
Previously we have described the evolution of a highly tractable
series of GR agonists with lower lipophilicity. These originated
from a tetrahydronaphthalene aryl pyrazole series9 represented
by 3 (NFkB pIC50 8.8 (108%)) (Fig. 1). With the aid of modelling,
we successfully discovered a tractable replacement for the tetrahy-
dronaphthalene with increased polarity as represented by the
ethyl benzene sulfonamide 4 which proved the starting point for
the development of orally active agonists.10,11
As previously described,9 examination of the hydrogen-bonding
interactions of the amino-pyrazole 3 showed that that there was a
hydrogen bond between one of the hydrogen atoms on the amino
group and the oxygen of the proximal carbonyl of the amide form-
ing a six membered ring. We were intrigued as to whether replac-
ing the hydrogen bond with bicyclic systems such as the
pyrazolopyrimidine 5 or indazole 6 would show functional activity
(and potentially increased activity) particularly when combined
with the new sulfonamide left hand side.
Fluticasone furoate 2 is a fully efficacious sub-nanomolar GR
agonists in a cellular NFjB assay with pIC50 potency of 10.4
(108%) (cf. dexamethasone pIC50 9.0 (102%)). This extremely high
potency means that only very small doses of drug are used in the
clinical setting (e.g., a total of 110
l
g per is administered once daily
The pyrazolopyrimidine sulfonamide 13 was prepared by
initially protecting the known aminopyrazolopyrimidine12 as its
t-butyl carbamate 9. Deprotonation and reaction with the
epoxytosylate13 10 gave the epoxide 11 which was opened with
ethylamine and the resultant secondary amine sulfonylated to give
13 (Scheme 1).
for adults).3 One aspect of our programme of research activities
into glucocorticoid agonists is to investigate whether agonists of
* Corresponding author.
E-mail address: simon.jf.macdonald@gsk.com (S.J.F. Macdonald).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.020

K. Biggadike et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4846–4850
4847
F
S
O
H
OH
O
O
OH
N
N
HO
H
N
O
H
N
N
CF3
N
H
N
CF3
S
H2N
A
O
F
F
O
O
O
N
H
H
4
3
1 fluticasone propionate
F
OH
OH
S
O
H
N
O
H
N
O
N
N
O
H
N
N
N
CF3
N
CF3
O
S
S
H
O
O
N
O
O
N
A
F
F
H
O
5
6
2 fluticasone furoate
Figure 1. Steroidal (1–2) and non-steroidal glucorticoid agonists (3–6).
O
N
O
O
O
10
O
NH
NH2
N
N
O
N
F3C
OTs
F3C
d,e
a,b
c
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
11
9
8
O
S
O
OH
OH
N
HN
NH
N
NH
f
F3C
F3C
N
N
F
N
N
N
N
N
Ph
Ph
12
13
Scheme 1. Reagents: (a) (tBuO2C)2O (2 equiv), 4-dimethylaminopyridine, THF; (b) aqueous KOH or silica gel, 80% over two steps; (c) 10, NaH, DMF, 35%; (d) EtNH2, MeCN; (e)
i
CF3CO2H, CH2Cl2; (f) FC6H4SO2Cl, Pr2NEt, CH2Cl2, 32% yield over three steps.
4-Amino-6-methyl-N-aryl indazoles (and related analogues
which are not commercially available) were made according to the
routed exemplified in Scheme 2. Methyldibromobenzaldehyde14
14 was converted to the arylhydrazone 15 prior to a palladium cat-
alysed cyclisation and then a palladium catalysed amination to af-
ford 17.15
The aryl indazoles were then reacted with the epoxytosylate 10
mediated by bismuth(III) chloride to give the tosylate 19 which
was converted into the corresponding epoxides 20 using polymer
supported carbonate resin. Epoxide opening with a primary amine
was followed by acylation or sulfonylation to give the target com-
pounds represented by 22 (Scheme 3).
A functional GR agonist assay was carried out using human
A549 lung epithelial cells.9 This assay allows determination of
the ability of compounds to repress transcription (i.e., transpres-
sion). Efficacy is expressed as a percentage of the dexamethasone
response.16
Br
Br
N
N
H
F
CHO
Br
a
b
Br
Based on the 5-aminopyrazole derivative 7 it was decided to
initially replace the intramolecular hydrogen bond between the
pyrazole NH2 and the carbonyl of the amide with a bicyclic system
such as the pyrazolopyrimidine 13 (the 6-methyl group being in-
14
15
Br
NH2
N
c,d
N
cluded for ease of synthesis). In the transrepression NFjB assay
N
N
both 7 and 13 have equivalent potency and efficacy (Table 1).16
The isosteric indazole 23 showed a half log unit increase in activity
to NFjB pIC50 8.1, and given measured lipophilicity values of pyr-
16
17
F
F
azolopyrimidines and indazoles are similar, and given also the in-
creased tractability of the indazoles, we switched predominantly to
this series.
Attention was then focussed on the sulfonamide linker group in
the indazoles and the nature of the N-substituent referred to as the
Scheme 2. Reagents: (a) 4-FC6H4NHNH2, NaOAc, MeOH, 85%; (b) racemic 1,10-[1,10-
binaphthalene]-2,20-diylbis[1,1-diphenylphosphine (BINAP), tris(dibenzylideneace-
tone)dipalladium (Pd2(dba)3), PhMe, 39%; (c) NaOtBu, racemic BINAP, Pd2dba3,
PhC(NH)Ph, PhMe; (d) aqueous HCl, THF, 79% over two steps.

4848
K. Biggadike et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4846–4850
OH
O
NH2
O
F3C
10
OTs
TsO
NH
NH
F3C
F3C
N
a
b
R6
N
N
N
R6
R6
Ar
N
N
18
Ar
Ar
19
20
R1
R1
OH
OH
F3C
N
N
NH
NH
R2
H
c
d
F3C
N
N
6
R6
N
N
21 R
Ar
Ar
22
Scheme 3. Reagents: (a) 1, BiCl3, CH2Cl2; (b) polymer supported carbonate resin, CH2Cl2; (c) R1NH2, MeCN; (d) R2CO2H, 1-[bis(dimethylamino)methylene]-, 3-oxide 1H-1,2,3-
i
i
i
triazolo[4,5-b]pyridinium hexafluorophosphate (HATU), Pr2NEt, DMF or R2COCl, Pr2NEt, THF, or R2SO2Cl, Pr2NEt, CH2Cl2.
Table 1
Table 2
Comparison of indazole sulfonamides with indazole amides and trigger (R1) groups
(all compounds racemic unless otherwise stated)a
Comparison of a phenyl pyrazole with its analogous pyrazolopyrimidine and indazole
(all compounds racemic unless otherwise stated)
H3C
CF3
OH
O
S
HO
N
CF3
X
N
O
R1
N
H
F
NH
Ba
% Max
N
N
Structure
NF
j
pIC50
nb
O
NH2
X
R1
NFkBa
% Max
7
13
23
7.5 0.1
7.6 0.1
8.1 0.1
86
91
94
6
3
6
8
N
N
pIC50
n
6
24
25
26
SO2
CO
CO
CO
Et
Et
8.6 0.4
9.1 0.3
8.3 0.2
8.5 0.1
98
107
98
8
2
3
6
6
4
7
8
Me
nPr
105
N
N
a
8
8
See Table 1 for notes.
N
N
H3C
Table 3
Comparison of the indazole substituents (all compounds racemic unless otherwise
stated)a
N
N
CF3
OH
R2
O
N
NH
H3C
R6
N
a
The efficacy maximal responses are quoted as a percentage of the maximum of
N
dexamethasone set at 100%.
Z
b
n = number of repeats.
R2
R6
Z
NFkBa
% Max
pIC50
N
‘R1 agonist trigger’ due to its profound ability to control the level of
24
27
28
29
30
31
32
33
H
H
H
H
F
F
F
F
F
H
Me
H
Me
H
Me
H
Me
H
H
Ph
Ph
4-FC6H4–
4-FC6H4–
Ph
9.1 0.3
9.4 0.2
9.1 0.2
9.4 0.3
9.5 0.2
9.6 0.3
9.7 0.2
9.7 0.4
9.9 0.1
7.5 0.2
107
108
104
105
102
106
106
106
105
91
2
5
5
5
6
3
4
6
2
6
4
5
8
8
8
8
6
8
8
8
agonist (NFj
B) potency17 (Table 2). Replacing the sulfonamide
with an amide results in a 0.5 log unit jump in agonist potency;
this together with the greater commercial availability of acids
and the reduced lipophilicity of amides compared with sulfona-
mides (clog P values are ca. 0.5 units lower) led to switching to
the amide series. Comparing methyl, ethyl and n-propyl, the most
potent agonist trigger proved to be ethyl (as in 24)—this trigger
Ph
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
32E1b
32E2b
F
combined with an amide linker gave dexamethasone like NF
jB po-
a
tency with a pIC50 9.1 (107%).10,18
See Table 1 for notes.
E1 and E2 indicate enantiomer 1 and 2 of the racemate respectively.
b
Some simple substitutions on the phenyl indazole whilst keep-
ing the left hand aryl amide as either the phenyl amide or the o-
fluoroaryl amide both with an R1 ethyl agonist trigger were then
investigated (Table 3). Previous SAR suggested the 6-position of
the indazole should be investigated whilst previous literature19
suggested inclusion of a para-fluoro on the aryl ring attached to

K. Biggadike et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4846–4850
4849
the indazole N1. Whilst none of these changes alone make a sig-
nificant difference, in combination, potency does increase. Thus
introduction of a para-fluoro in the aryl group attached to N1 of
the indazole has almost no effect on the potency (compare 24
a
Y735
Q642
M646
R611
NF
j
B pIC50 9.1 with 28 NF
jB pIC50 9.1 or compare 31 NFjB
pIC50 9.6 with 33 NF
j
B pIC50 9.7). On replacing the R6 indazole
hydrogen with a methyl group there is a trend for slight increase
in potency with the less potent compounds. For example, compare
24 NF
9.7 with 33 NF
j
B pIC50 9.1 and 27 NF
jB pIC50 9.4 and then 32 NFjB pIC50
j
B pIC50 9.7. In fact the R2 substituent on the benz-
T739
amide probably contributes most to potency with a trend of
around a 0.3 increase in activity when an ortho-fluorine is incor-
Q570
N564
porated. For example, compare 24 NF
j
B pIC50 9.1 with 30 NF
jB
pIC50 9.5 or 29 NF B pIC50 9.4 with 33 NF
j
jB pIC50 9.7. The most
potent compounds are 32 and 33 both with pIC50 potencies of 9.7.
Separation of the enantiomers20 of 32 gave 32E1 (enantiomer 1)
b
with an NFjB pIC50 9.9 and with the second enantiomer 32E2
still active but significantly less potent with an NFjB pIC50 7.5.
These findings led to a final round of optimisation where substi-
tution of the benzamide was explored.
Optimisation of benzamide substitution was carried out with
the p-fluoroarylindazole with R6 = H (as in 32) given the similari-
ties in potency with R6 = methyl (as in 33). A wide range of benz-
amide substituents were prepared (Table 4 shows a selection).
Meta and para substituents whilst tolerated, are several orders of
magnitude less potent (for example m-CF3 and p-Et have pIC50
7.6 (106%) and 7.7 (104%) respectively). Similarly polar ortho sub-
stituents, in a related series,10 whilst active are much less potent. A
variety of lipophilic ortho substituents are much preferred such as
34 methyl (pIC50 9.5) or 35 chloro (pIC50 9.6). Di-ortho substitution
such as 36 2,6-dimethyl (pIC50 9.3), 37 2,6-difluoro (pIC50 9.5) and
38 2,6-dichloro (pIC50 9.9) are similarly active to the mono-substit-
uents as racemates. These di-chloro compounds were separated
into their enantiomers20 with the most potent enantiomer being
c
38E1 the 2,6-dichloro analogue with NFjB pIC50 10.1 (105%)—in
the same potency range as fluticasone furoate (pIC50 10.4). This
represents one of the most potent non-steroidal glucocorticoid
agonist reported to date.
The aryl pyrazole 39 (a direct analogue of the indazole 38E1) has
been crystallised in the GR ligand binding domain and has been re-
ported recently.21 This structure (Fig. 2a) clearly shows the posi-
O
Cl
OH
N
N
Table 4
N
Optimisation of benzamide substituents (all compounds racemic unless otherwise
N
H
CF3
stated)a
H2N
Cl
O
CF3
OH
39
F
O
N
Figure 2. (a) Crystal structure ligand orientation for aryl pyrazole 39 (in green).
Hydrogen bonds are shown as dotted yellow lines. (b) Docking pose for 38 (in
orange) in the crystal structure protein; note the minimal side chain movement
from crystal structure form; (c) Structures for 38 and 39 superimposed (for clarity
side chains for crystal form only shown).
R
NH
H3C
R6
N
N
tioning of the arylpyrazole, the central trifluoromethyl and
hydroxyl groups, the terminal benzamide moiety and three hydro-
gen bonds holding the ligand in the site. The possible impact of
cyclisation was explored through docking experiments using the
protein from the pyrazole crystal structure and docking into this
protein the directly equivalent structure from the indazole series
(38). Docking was carried out using Flo+21 and allowed all the side
chains in the active site the freedom to move. It can be seen
(Fig. 2a–c) that cyclisation has minimal impact on the placement
of the ligand in the site with all portions of the molecule assuming
similar positions and the three hydrogen bonds retained. This is
perhaps unsurprising given the 6-membered ring caused by intra-
molecular hydrogen-bonding between the NH2 group on the pyra-
zole and the carbonyl of the amide.20
F
R
R6
NFkBa
% Max
pIC50
n
32
34
35
36
37
38
2-F
2-Me
2-Cl
2-Me, 6Me
2-F, 6-F
2-Cl, 6-Cl
2-Cl, 6-Cl
2-Cl, 6-Cl
H
H
H
H
H
H
H
H
9.7 0.2
9.5 0.2
9.6 0.3
9.3 0.4
9.5 0.3
9.9 0.2
10.1 0.1
8.0 0.2
106
108
103
109
109
105
105
98
4
6
4
6
7
2
5
7
6
6
8
8
8
4
38E1b
38E2b
16
15
a
See Table 1 for notes.
b
E1 and E2 indicate enantiomer 1 and 2 of the racemate respectively.

4850
K. Biggadike et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4846–4850
Unsubstituted
Monochloro
Dichloro
50
70
85
Δ
Δ
E
E
Δ
E
kJ/mol
kJ/mol
kJ/mol
0
0
0
0
160
320
0
160
320
0
160
320
Torsion
Torsion
Torsion
Figure 3. Changes in energy against torsional scans for the unsubstituted 28, mono-chloro 35 and dichloro 38 indazole derivatives around the benzamide phenyl to carbonyl
bond. Increments of 10° were used for the scan and for each step in the scan the structures were allowed to minimise whilst holding the torsion fixed. Energies are relative to
the lowest value found in the scan.
8. Schacke, H.; Berger, M.; Hansson, T. G.; McKerrecher, D.; Rehwinkel, H. Exp.
It was noted that ortho substitution of the benzamide phenyl
ring had a positive effect on the agonist activity of the indazoles.
Opin. Ther. Patents 2008, 18, 339; Takaashi, H.; Razavi, H.; Thomson, D. Curr.
Top. Med. Chem. 2008, 8, 521; Mohler, M. L.; He, Y.; Wu, Z.; Hong, S.-S.; Miller, D.
Conformational analysis was performed to explore the effect of
ortho substitution. Torsional scans were performed around the
phenyl to carbonyl bond for the unsubstituted 28, o-chloro 35
and o-dichloro 38 analogues using Macromodel and the OPLS
2005 force field. The results are presented as torsional plots
(Fig. 3). For the more potent compounds (mono-ortho 35 and di-
ortho 38) it is clear that the preferred conformation has the phenyl
ring orthogonal—twisted at ꢀ90°—to the plane of the carbonyl,
which is also the conformation found in the crystal structure
(Fig. 2).21 The conformational preferences are the same for both,
but the energy well for the dichloro derivative is deeper. The
unsubstituted derivative shows a rather different pattern. The
same orthogonal twisted conformations are available, but the well
is much broader with many more additional conformations acces-
sible. This greater conformational freedom could be the cause of
the lower activity seen with the unsubstituted compounds.
In summary, this paper describes the discovery of highly potent
non-steroidal glucocorticoid agonists. The dichloro derivative 38E1
has a profile consistent with inhaled steroidal glucocorticoid
drugs—it is extremely potent, has high lipophilicity and molecular
weight. This physicochemical profile, whilst unsuitable for drugs
dosed by the oral route, are in fact frequently found in inhaled ste-
roidal glucocorticoids on the market today.22
D. Exp. Opin. Ther. Patents 2007, 17, 37. These papers provide succinct reviews of
the non-steroidal GR agonist and contain many leading references.
9. Clackers, M.; Coe, D. M.; Demaine, D. A.; Hardy, G. W.; Humphreys, D.; Inglis, G.
G. A.; Johnston, M. J.; Jones, H. T.; House, D.; Loiseau, R.; Minick, D. J.; Skone, P.
A.; Uings, I.; McLay, I. M.; Macdonald, S. J. F. Bioorg. Med. Chem. Lett. 2007, 17,
4737.
10. Barnett, H. A.; Coe, D. M.; Cooper, A. W. J.; Jack, T. I.; Jones, H. T.; Macdonald, S.
J. F.; McLay, I. M.; Rayner, N.; Sasse, R. Z.; Shipley, T. S.; Skone, P. A.; Somers, G.
I.; Taylor, S.; Uings, I. J.; Woolven, J. M.; Weingarten, G. G. Bioorg. Med. Chem.
Lett. 2009, 19, 158.
11. Akouvi, O.; Heather Barnett, H.; Biggadike, K.; Coe, D. M.; Cubbage, K.; Diallo,
H.; Evans, D.; Hardy, G. W.; Humphreys, D.; Jones, H. T.; Macdonald, S. J. F.;
McLay, I. M.; Rayner, N.; Shipley, T.; Skone, P. A.; Uings I.;Weingarten, G. G.
Bioorg. Med. Chem. Lett., manuscript in preparation.
12. Biggadike, K.; House, D.; Inglis, G. G. A.; Macdonald, S. J. F.; McLay, I. M.; Skone,
P. A. PCT Int. Appl. WO2007054294, 2007.
13. Keeling, S. P.; Campbell, I. B.; Coe, D. M.; Cooper, T. W. J.; Hardy, G. W.; Jack, T.
I.; Jones, H. T.; Needham, D.; Shipley, T. J.; Skone, P. A.; Sutton, P. W.;
Weingarten, G. A.; Macdonald, S. J. F. Tetrahedron Lett. 2008, 49, 5101.
14. Lulinski, S.; Serwatowski, J. J. Org. Chem. 2003, 68, 5384.
15. Eldred, C. D.; House, D.; Inglis, G. G. A.; Macdonald, S. J. F.; Skone, P. A. PCT Int.
Appl. WO 2006108699, 2006.
16. The compounds were tested for their ability to bind to GR using competition
experiments with fluorescent-labelled dexamethasone (see Ref. 9). The tight
binding limit of the assay is about pIC50 8.5. pIC50 values of all the analogues
described here are between 7.5 and 8.5. All compounds described show
excellent selectivity over other nuclear receptors (androgen, progesterone and
estrogen receptors) with pIC50 values in the respective binding assays showing
50–1000 fold selectivity over GR. All the compounds described are full agonists
in a transactivation assay (see Ref. 9).
17. Barker, M.; Clackers, M.; Copley, R.; Demaine, D. A.; Humphreys, D.; Inglis, G. G.
A.; Johnston, M. J.; Jones, H. T.; Haase, M. V.; House, D.; Loiseau, R.; Nisbet, L.;
Pacquet, F.; Skone, P. A.; Shanahan, S. E.; Tape, D.; Vinader, V. M.; Washington,
M.; Uings, I.; Upton, R.; McLay, I. M.; Macdonald, S. J. F. J. Med. Chem. 2006, 49,
4216.
18. A similar pattern of agonist trigger potency was observed in the aryl pyrazole
series (see Ref. 9).
19. Hannah, J.; Kelly, K.; Patchett, A. A.; Steelman, S. L.; Morgan, E. R. J. Med. Chem.
1975, 18, 168.
20. Compound 32 was separated into its enantiomers 32E1 and 32E2 on a 25 cm
Chiralpak AD column eluting at 1 mL/min with 50% ethanol in heptane
containing 0.1% trifluoroacetic acid over 30 min. 32E1 eluted around 9.0 min
and 32E2 eluted around 16.3 min. 38 was separated into its enantiomers 38E1
and 38E2 on a 25 cm Chiralpak AD column eluting at 1 mL/min with 40%
ethanol in heptane over 30 min. 38E1 eluted around 5.4 min and 38E2 eluted
around 9.1 min.
21. Madauss, K. P.; Bledsoe, R. K.; Mclay, I.; Stewart, E. L.; Uings, I. J.; Weingarten,
G.; Williams, S. P. Bioorg. Med. Chem. Lett. 2008, 18, 6097.
22. Ritchie, T.; Luscombe, C. N.; Macdonald, S. J. F. J. Chem. Inf. Model. 2009, 49, 1025.
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