Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.08.070

11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.

Full text of DOI:10.1016/j.bmcl.2012.08.070

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6756–6761
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Optimisation of pharmacokinetic properties in a neutral series of 11b-HSD1
inhibitors
⇑
James S. Scott , Adrian L. Gill, Linda Godfrey, Sam D. Groombridge, Amanda Rees, John Revill,
Paul Schofield, Pernilla Sörme, Andrew Stocker, John G. Swales, Paul R. O. Whittamore
Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
11b-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other
elements of the metabolic syndrome. In this program of work we describe how a series of neutral
2-thioalkyl-pyridine 11b-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties
to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine.
A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from
sulfur to carbon substitution.
Received 31 July 2012
Revised 14 August 2012
Accepted 16 August 2012
Available online 5 September 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
11b-HSD1 inhibitors
Pharmacokinetics
Reactive metabolites
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an
NADPH dependent reductase expressed mainly in liver, adipose
and brain tissue that converts the glucocorticoid inactive hormone
cortisone to the glucocorticoid active hormone cortisol.1 It has
been postulated that elevated intracellular levels of the glucocorti-
coid hormone cortisol can lead to glucose intolerance and insulin
resistance and could play a key role in the development of the met-
abolic syndrome.2–4 Inhibition of 11b-HSD1 has been viewed as a
potential therapeutic intervention that could reduce intracellular
glucocorticoid concentrations and in turn have beneficial effects
in patients with the metabolic syndrome.5–7 A significant research
effort by both academic and industrial groups has led to a diverse
array of 11b-HSD1 inhibitors that has recently been reviewed.8–10
In previous publications, we have described our efforts to iden-
tify acidic inhibitors of 11b-HSD1 resulting in the development
candidates AZD401711 and AZD6925 (Fig. 1).12 In an attempt to in-
crease the chemical diversity of our program, we sought to identify
neutral inhibitors of the enzyme. Previously we had identified neu-
tral ligands11 but they had suffered from poor oral bioavailability
in rat due to high metabolic clearance. Pyridine 1, containing the
trans 4-hydroxy adamantylamine amide, was one of the most
potent compounds identified (IC50 7 nM) and, in stark contrast to
other neutral compounds profiled, showed at least some bioavail-
ability in rat (F 11%). This was therefore chosen as the start point
for our optimisation campaign. Our goals for this program were
to obtain neutral compounds that had: (i) sufficient mouse potency
to allow pharmacological evaluation in pre-clinical models;
(ii) good bioavailability in two species (rat and dog) to facilitate
robust dose to man predictions.
The synthetic routes towards the pyridines and pyrimidines
reported in this study are described in Schemes 1–5.13
4-Thiopropyl pyrimidines with variation in the R1 position
(Scheme 1) could be synthesized by a condensation between
diethyl 2-(ethoxymethylene)malonate 31 and amidines to form
dihydropyrimidines 32. Chlorination with phosphorous oxychlo-
ride gave 4-chloropyrimidines 33 that could be displaced with
propane thiolate to give 4-thiopyrimidines 34. Ester hydrolysis
under basic conditions to acids 35 was followed by HATU medi-
ated amide coupling to give pyrimidines 2, 4 and 10.
6-Methyl pyridines (Scheme 2) were synthesized by conversion
of 2-chloro-6-methylnicotinic acid 36 to amide 37 via formation of
the acid chloride followed by addition of trans-4-aminoadamantan-
1-ol. The 2-chloro substituent could be displaced with propane
thiolate to give pyridine 3 or converted using Suzuki chemistry with
cyclopropyl boronic acid to pyridine 19.
An alternative strategy that allowed diversity at R1 to be intro-
duced at the final step (Scheme 3) involved conversion of the di-
chloro pyridine 38 or pyrimidine 39 acid to the amides 40, 41 via
the acid chloride. Treatment with either propylthio or propoxy
nucleophiles resulted in a completely regioselective displacement
of the chloro group adjacent to the amide in both the pyridine
and pyrimidine to give intermediates 42–45. Displacement of the
remaining chloro group gave pyridines 5, 7, 9 and 21 and pyrimi-
dines 6, 8 and 30.
⇑
Corresponding author. Tel.: +44 1625 232567; fax: +44 1625 516667.
E-mail address: jamie.scott@astrazeneca.com (J.S. Scott).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.070

J. S. Scott et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6756–6761
6757
O
S
O
OH
O
S
O
OH
N
N
N
H
H
H
H
N
N
N
N
S
N
HO
H
AZD6925
AZD4017
1
O
Figure 1. Structures of AZD4017, AZD6925 and pyridine 1.
For pyrimidines containing a carbon substituted group at R2
(Scheme 4), the ring was constructed by taking b-keto esters of type
46 and condensing them with N,N-dimethylformamide dimethyl
acetal to form enamines of type 47. Subsequent condensation with
either methyl or morpholino substituted amidines formed pyrimi-
dines of type 48 and 49, respectively. Base mediated hydrolysis of
the ester groups gave acids of type 50 and 51 which could be cou-
pled with trans-4-aminoadamantan-1-ol under HATU mediated
coupling conditions to give pyrimidines 11–18 and 23–29.
In the case of pyridine 20, the ring was constructed by conver-
sion of b-keto ester 52 to enamine 53 followed by a Michael reac-
tion with methyl propiolate to give dienyl ester 54. Condensation
under basic conditions afforded the pyridone 55 which could be
converted to the chloropyridine 56 using phenyl dichlorophos-
phate. Ester hydrolysis to acid 57 was followed by HATU mediated
coupling with trans-4-aminoadamantan-1-ol to form amide 58.
Displacement of the chloro group with morpholine under micro-
wave irradiation gave pyridine 20 in good yield.
Based on crystallographic structural information and prior
structure–activity relationships (SAR),11 we knew that substitution
at the 6-pyridyl position was tolerated and elected to explore this
in both pyridine and pyrimidine sub-series as shown in Table 1. In
terms of human potency, the SAR for R1 substituents 1–10 was
notably flat across both sub-series, with arguably the NMe and
NMe2 groups showing small increases in potency. In the case of po-
tency against the mouse enzyme however, dramatic improvements
(>30-fold) were seen upon 6-substitution in the pyridine series
with NHMe 5, NMe2 7 and morpholine 9 and to a lesser extent
(fourfold) with methyl 3. The pyrimidine sub-series showed the
same trend in terms of rank order of substituents (NHMe, NMe2,
morpholine ꢀ Me > H) although these were always less potent
than the corresponding pyridine matched pairs. Pleasingly, and
in contrast to the unsubstituted compounds 1 and 2, methyl (3,
4) and morpholine (9, 10) substitution resulted in good pharmaco-
kinetic properties in both the pyridine and pyrimidine sub-series
whereas the NHMe 5 and NMe2 7 pyridines showed more modest
improvements.
O
O
O
a
b
OEt
OEt
31
EtO
OEt
O
N
OEt
N
c
O
R1
N
R1
N
Cl
H
33
32
OH
O
S
O
e
OR
N
N
N
H
R1
d
N
R1
N
S
2 R1=H
4 R1=Me
10 R1=morpholine
R=Et 34
R=H 35
Scheme 1. Synthesis of pyrimidines 2,4 and 10. Reagents and conditions:
(a) R1C(@NH)NH2, NaOMe, MeOH,
D, 4 h, 42–64%; (b) POCl3, D, 3 h, 45–100%;
(c) nPrSH, Na2CO3, DMF, 60 °C, 30 min, 62–92%; (d) NaOH, MeOH/H2O, 25 °C, 2 h,
65–100%; (e) trans 4-hydroxy adamantylamine, HATU, N(iPr)2Et, DMF, 25 °C, 3 h,
16–74%.
OH
OH
O
O
O
S
a
OH
b
N
N
H
H
N
Cl
N
Cl
N
36
37
3
c
OH
O
N
H
N
19
Scheme 2. Synthesis of pyridines 3 and 19. Reagents and conditions: (a) (i) Oxalyl
chloride, DMF, CH2Cl2, 20 °C, 16 h; (ii) trans-4-aminoadamantan-1-ol, (iPr)2NEt,
THF, 20 °C, 16 h, 31%; (b) nPrSH, Na2CO3, DMA, 60 °C, 3 h, 54%; (c) cPrB(OH)2,
Pd(OAc)2, PCy3, K3PO4, toluene/H2O, 100 °C, 16 h, 27%.
OH
OH
OH
O
O
O
O
X
N
b
a
c
X
N
X
OH
X
N
H
H
H
R1
N
S
Cl
N
S
Cl
N
Cl
Cl
N
Cl
38 X=CH
39 X=N
40 X=CH
41 X=N
42 X=CH
43 X=N
d
5 X=CH; R1=NHMe
6 X=N; R1=NHMe
7 X=CH; R1=NMe2
8 X=N; R1=NHMe2
9 X=CH; R1=morpholine
OH
OH
O
O
O
e
X
N
X
N
H
H
N
O
N
Cl
N
O
44 X=CH
45 X=N
21 X=CH
30 X=N
Scheme 3. Synthesis of pyridines 5, 7, 9, 21 and pyrimidines 6, 8 and 30. Reagents and conditions: (a) (i) Oxalyl chloride, DMF, CH2Cl2, 20 °C, 16 h; (ii) trans-4-
aminoadamantan-1-ol, (iPr)2NEt, THF, 0 °C, 4 h, 66%; (b) nPrSH, Na2CO3, DMA, 25 °C, 4 h, 49–90%; (c) R1H, THF, 150 °C, W, 6 h, 54–96%; (d) nPrOH, NaHMDS, 150 °C,
W, 2 h,
82–85%; (e) morpholine, 150 °C, W, 10 h, 34–83%.
l
l
l

6758
J. S. Scott et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6756–6761
OH
O
O
O
O
a
b
d
N
N
OR
R2
N
OEt
OEt
R2
H
Me2N
N
R2
N
O
R2
O
11 R2=nBu
12 R2=tBu
13 R2=CH2 Pr
15 R2=CH2 Pn
16 R2=Ph
17 R2=cPr
c
46
47
R=Et 48
R=H 50
c
i
e
14 R2=CH2cPr 18 R2=cPn
OH
O
O
d
N
N
23 R2=Me
24 R2=tBu
25 R2=cPr
26 R2=cBu
27 R2=cPn
OR
R2
N
H
28 R2=cHex
29 R2=1-MecPr
N
N
R2
N
N
O
O
R=Et 49
R=H 51
c
Scheme 4. Synthesis of pyrimidines 11–18 and 23–29. Reagents and conditions: (a) Me2NCH(OMe)2, 1,4-dioxane, 100 °C, 7 h, 93–99%; (b) MeC(@NH)NH2ÁHCl, NaOMe,
MeOH, 80 °C, 4 h, 61–67%; (c) NaOH, MeOH/H2O, 60 °C, 2 h, 81–96%; (d) trans-4-aminoadamantan-1-ol, HATU, N(iPr)2Et, DMF, 20 °C, 3 h, 14–72%; (e) (N-morpho-
lino)C(@NH)NH2ÁHBr, NaOMe, MeOH, 80 °C, 6 h, 61–67%.
O
O
O
O
O
b
c
a
OMe
OMe
OMe
MeO
OMe
OH
O
H2N
O
N
H2N
H
55
52
53
54
d
OH
O
O
O
f
g
OR
N
N
H
H
Cl
N
N
N
Cl
N
O
20
58
R=Me 56
R=H 57
e
Scheme 5. Synthesis of pyridine 20. Reagents and conditions: (a) NH4OAc, MeOH, 25 °C, 48 h, 90%; (b) CH„CCOOMe, toluene, 100 °C, 20 h, 31%; (c) NaOtBu, N-methyl-2-
pyrrolidone, 145 °C, 30 h, 71%; (d) PhOP(@O)Cl2, 180 °C, 10 min, 53%; (e) NaOH, MeOH/H2O, 25 °C, 3 h, 100%; (f) trans-4-aminoadamantan-1-ol, HATU, N(iPr)2Et, DMF, 25 °C,
2 h, 85%; (g) morpholine, THF, 150 °C, lW, 10 h, 83%.
The methyl and morpholine compounds were evaluated in a
dog pharmacokinetic study as shown in Table 4. The methyl pyrim-
idine 4 showed an excellent pharmacokinetic profile whereas the
corresponding pyridine 3 showed much lower exposure despite
similar clearance values. The morpholine compounds 9 and 10
showed higher clearances with the pyrimidine 10 having low bio-
availability in contrast to the pyridine 9 which had no detectable
oral levels. The methyl pyrimidine 4 was therefore chosen as an
initial lead on the basis of having good pharmacokinetics in both
rat and dog with the key challenge being to improve the mouse
potency.
A metabolism-ID study on pyrimidine 6 indicated that the
majority of the metabolism (86% by peak area) was oxidation of
the nPr group with no glucuronidation of the hydroxyl adamantyl
group observed. Alarmingly however, small amounts of com-
pounds corresponding to glutathione trapping and thio de-alkyl-
ation were observed indicating bioactivation of the thiopropyl
group (Scheme 6). This was in direct contrast to the pyridine series
where no such metabolism had been observed and was presum-
ably a consequence of the increased electron deficiency of the
pyrimidine ring. We felt that this presented a potential toxicolog-
ical risk and therefore decided to explore replacing the thio-group
with a carbon based substituent in order to circumvent this issue
(Table 2).
expected based on previous SAR.11 Efforts to increase steric bulk
by moving to a tert-butyl substituent 12 resulted in a loss of activ-
ity and further exploration of branched alkyl chains (13–15) re-
sulted in minimal improvements. Phenyl 16 was poorly tolerated
however, cyclopropyl 17 resulted in an increase in potency in both
human (IC50 395 nM) and mouse (IC50 8.2 lM). Expanding the ring
size to cyclopentyl 18 brought further improvements in human po-
tency (IC50 68 nM) but a loss of mouse activity.
The pyridine variant 19 of the cyclopropyl compound was found
to be potent in human (IC50 107 nM) and was significantly more
active against the mouse enzyme (IC50 139 nM) than any of the
pyrimidines. All of the six compounds tested showed good phar-
macokinetics in rat. The two most potent compounds 18 and 19
were also profiled in dog (Table 4). The pyrimidine again showed
superior pharmacokinetics relative the pyridine with significantly
lower clearance being observed.
The SAR of non thioalkyl substituents was also examined in the
N-morpholino substituted pyridine and pyrimidine series (Table 3)
in an effort to increase potency against the mouse enzyme. In the
morpholino-pyridine series, cyclopropyl 20 was more potent than
its matched pair 19 in the methyl-pyridine series and was the first
compound in this series to be more active in mouse than in human.
The direct replacement of the sulfur atom present in 9 with oxygen
(compound 21), showed slightly reduced potency in human but
retained mouse potency. Notably, the measured lipophilicty of
the ether 21 (logD7.4 3.8) was surprisingly higher than the
The direct replacement of the sulphur atom present in 4 with
carbon (compound 11) resulted in a dramatic loss of potency as

J. S. Scott et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6756–6761
6759
Table 1
OH
O
X
N
H
R1
N
S
Entry
X
R1
Human 11b-HSD1
Mouse 11b-HSD1
logD7.4
Rat heps clint
(l
L/min/106 cells)
Rat Cl
(mL/min/kg)
Rat bioavailability (%)
IC50a
(
lM)
a
IC50
(lM)
1
2
3
4
C
0.007
0.009
0.007
0.010
0.922
2.049
0.233
1.509
2.3
2.0
2.8
2.5
49
87
44
11
110
100
13
11
0
H
N
C
H
63
74
Me
Me
N
14
N
5
6
7
C
N
C
0.003
0.004
0.002
0.019
0.029
0.026
3.3
2.9
3.8
34
69
73
36
—
25
—
H
N
H
N
N
30
24
8
9
N
C
0.004
0.004
0.335
0.025
3.4
2.9
29
6
—
—
N
N
17
64
O
O
10
N
0.011
0.191
2.8
3
11
83
a
Homogeneous time resolved fluorescence assay (HTRF) assay based on mean n >3 results.
OH
OH
OH
OH
O
S
O
S
O
O
N
H
N
N
N
N
H
N
H
N
N
H
+
+
N
H
N
N
N
N
N
SH
H2N
N
SH
H
H
Glut
4%
7%
2%
Scheme 6. Metabolism-ID on pyrimidine 6 in rat hepatocytes indicating bioactivation of the thiopropyl group.
corresponding thioether 9 (logD7.4 2.9). This could be attributable
to the potential formation of a 6-membered ring intramolecular
hydrogen bond between the ether oxygen and the amide NH
reducing the polarity of both the ether and the amide NH substit-
uents. In the morpholine-pyrimidine series, the methyl and tert-
butyl substituents 23 and 24 had poor potency against the human
and mouse isoforms. Carbocyclic rings (3–6 membered) 25–28
were profiled and showed interesting species differences. In terms
of human potency, increasing rings size (3?5) adds potency with
the cyclopentyl 27 being optimal (IC50 22 nM). Further expansion
to the cyclohexyl 28 resulted in a decrease in human potency. In
terms of mouse potency, the SAR was orthogonal in that the small-
est substituent, cyclopropyl 25 was optimal and increasing ring
size (3?6) reduced mouse potency. Attempts to further substitute
the cyclopropyl ring 29 had little effect on human potency but
resulted in an order of magnitude reduction in mouse potency.
The oxygen analogue 30 in the morpholine-pyrimidine series was
found to have reasonable activity against both human and mouse,
but had only mediocre rat pharmacokinetics and was not pro-
gressed further.
clearance, pyridine 20 showed only moderate pharmacokinetics,
however, the profile of pyrimidine 25 was excellent with low clear-
ance (Clp 8.6 mL/min/kg) and complete bioavailability (F 100%).
Further profiling of compound 25 demonstrated an attractive
profile. The compound was inactive (<25% inhibition at 10 lM)
against five isoforms of the cytochrome P450 enzymes (CYP1A2,
CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and showed no detectable
activity in the hERG IonWorks assay (Table 5). Plasma protein
binding showed very high free levels that compensated for the
moderate enzyme potency. The solubility as measured on crystal-
line material was 240 lM and when coupled with good cellular
permeability as measured in an MDCK assay (Papp(A–B)
19 Â 10À6 cm sÀ1; efflux ratio 1.7), it was predicted that this would
lead to good absorption in vivo. Importantly, compound 25 dis-
played excellent selectivity against the related anti-target 11-
bHSD2 (IC50 >30 l
M)14 indicating that this compound was unlikely
to lead to hypertensive effects associated with inhibition of this
enzyme.15
In conclusion, we have optimised a neutral pyrimidine series of
11b-HSD1 inhibitors to obtain compounds with good potency
against human and mouse isoforms and with good pharmacokinet-
ics in rat and dog as exemplified by compound 25. A potential reac-
tive metabolite issue with 4-thioalkyl-pyrimidines was identified
Compounds 20 and 25 were identified as the most promising
candidates in terms of potency across both species and rat pharma-
cokinetics, and were profiled in dog (Table 4). Despite low in vivo

6760
J. S. Scott et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6756–6761
Table 2
OH
O
X
N
H
N
R2
Entry
11
X
R
Human 11b-HSD1
Mouse 11b-HSD1
logD7.4
1.6
Rat heps clint
Rat Cl
(mL/min/kg)
Rat bioavailability (%)
98
(uL/min/106cells)
a
a
IC50
2.10
>8.0
(l
M)
IC50
(lM)
N
>30
3
9.5
12
13
14
15
N
N
N
N
17.8
>30
>30
>30
1.9
1.4
1.2
2.1
<2
—
5
4.4
13
—
84
100
—
0.644
1.48
0.847
7
17
50
16
17
18
N
N
N
C
14.8
>30
8.2
1.1
1.2
2.0
1.6
11
<2
7
—
—
0.395
0.068
0.107
—
—
>30
6.6
8.6
77
75
19
0.139
<2
a
Homogeneous time resolved fluorescence assay (HTRF) assay based on mean n >3results.
Table 3
OH
O
X
N
H
N
N
R2
O
a
a
Entry
X
R2
Human 11b-HSD1 IC50
M)
Mouse 11b-HSD1 IC50
M)
logD7.4 Rat heps clint (uL/min/
106cells)
Rat Cl (mL/min/
kg)
Rat bioavailability
(%)
(l
(l
20
21
C
C
0.021
0.014
0.006
0.019
2.0
3.8
<2
15
21
33
100
31
O
23
24
N
N
5.67
3.18
3.45
17.0
1.2
2.6
<2
<2
—
—
Me
4.8
100
25
26
N
N
0.102
0.060
0.095
0.264
2.1
2.4
<2
<2
8.1
11
100
45
27
N
0.022
0.784
3.0
3
7.6
67
28
29
30
N
N
N
0.080
0.137
0.028
0.831
1.11
3.2
1.8
3.0
6
5.8
—
31
—
<2
9
O
0.078
14
36
a
Homogeneous time resolved fluorescence assay (HTRF) assay based on mean n >3results.

J. S. Scott et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6756–6761
6761
Table 4
Dog pharmacokinetic parameters
Entry
Dog heps clint (uL/min/106cells)
Clpa (mL/min/kg)
Vdss (L/kg)
Cmax
(l
M)
PO half-life (h)
IV half-life (h)
Bioavailability (%)
3
4
9
10
18
19
20
25
18
5.8
40
12
4.6
<2
11
9.9
18
17
3.5
17
0.4
0.3
0.5
0.7
0.9
0.3
0.6
0.9
0.15
0.49
—
0.04
0.17
0.26
0.04
0.36
0.7
0.6
—
0.9
6.7
1.7
5.7
2.7
0.5
0.4
0.4
0.7
3.5
0.3
1.1
1.7
5
110
0
10
58
37
25
100
24
5.3
7.9
8.6
a
Compounds were dosed IV/PO at 1 mg/kg in 5% DMSO: 95% hydroxypropyl b cyclodextrin. Data is mean of two animals (male and female) in a single experiment.
Table 5
Physical properties of compound 25
Aqueous solubilitya pH 7.4 (
240
l
M)
hERG IC50
>100
(lM)
Rat PPBb (% free)
>57
Dog PPBb (% free)
43
Human PPBb (% free)
38
MDCKc permeability Papp (Â10À6 cm sÀ1
19 (A–B); 30 (B–A)
)
a
b
c
Solubility of compounds in aqueous phosphate buffer at pH 7.4 after 24 h at 25 °C (
PPB was assessed by equilibrium dialysis in the appropriate species plasma at 37 °C. Free and bound concentrations were quantified by LC–UVMS.
Compounds were incubated at 10 M in cultured MDCK cells. Permeability was measured in both the A to B and B to A direction.
lM).
l
6. Thieringer, R.; Hermanowski-Vosatka, A. Expert Rev. Cardiovasc. Ther. 2005, 3,
911.
and circumvented by a switch from sulphur to carbon substitution
followed by optimsation of this substituent. A key challenge in this
program was the co-optimisation of human and mouse potency
with the observed SAR being divergent.
7. Wamil, M.; Seckl, J. R. Drug Discov. Today 2007, 12, 504.
8. Webster, S. P.; Pallin, T. D. Expert Opin. Ther. Patents 2007, 17, 1407.
9. Boyle, C. D.; Kowalski, T. J. Expert Opin. Ther. Patents 2009, 19, 801.
10. Morgan, S. A.; Tomlinson, J. W. Expert Opin. Investig. Drugs 2010, 19, 1067.
11. Scott, J. S.; Bowker, S. S.; deSchoolmeester, J.; Gerhardt, S.; Hargreaves, D.;
Kilgour, E.; Lloyd, A.; Mayers, R. M.; McCoull, W.; Newcombe, N. J.; Ogg, D.;
Packer, M. J.; Rees, A.; Revill, J.; Schofield, P.; Selmi, N.; Swales, J. G.;
Whittamore, P. R. O. J. Med. Chem. 2012, 55, 5951.
12. Scott, J. S.; Barton, P.; Bennett, S. N. L.; deSchoolmeester, J.; Godfrey, L.; Kilgour,
E.; Mayers, R. M.; Packer, M. J.; Rees, A.; Schofield, P.; Selmi, N.; Swales J. G.;
Whittamore, P. R. O. Med. Chem. Commun. in press, http://dx.doi.org/ 10.1039/
C2MD20154B.
13. For experimental details of compounds described in this study see; Gill, A.;
Leach, A.; Packer, M. J.; Scott, J. S.; Sorme, P.; Swales, J. G.; Whittamore, P. R. O.
WO2009/130496.
14. Wilson, R. C.; Dave-Sharma, S.; Wei, J.; Obeyesekere, V. R.; Li, K.; Ferrari, P.;
Krozowski, Z. S.; Shackleton, C. H. L.; Bradlow, L.; Wiens, T.; New, M. I. Proc. Nat.
Acad. Sci. 1998, 95, 10200.
Acknowledgements
Nidhal Selmi is thanked for synthetic contributions and Gemma
Convey is thanked for the generation of biological data.
References and notes
1. Edwards, C. R. W.; Benediktsson, R.; Lindsay, R. S.; Seckl, J. R. Steroids 1996, 61,
263.
2. Björntorp, P.; Rosmond, R. Nutrition 2000, 16, 924.
3. Björntorp, P.; Holm, G.; Rosmond, R. Diabet. Med. 1999, 16, 373.
4. Walker, B. R. Eur. J. Endocrinol. 2007, 157, 545.
15. Kotelevtsev, Y.; Brown, R. W.; Fleming, S.; Kenyon, C.; Edwards, C. R. W.; Seckl,
J. R.; Mullins, J. J. J. Clin. Invest. 1999, 103, 683.
5. Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper,
M. S.; Hewison, M.; Stewart, P. M. Endocr. Rev. 2004, 25, 831.