Novel 2-imidazoles as potent and selective α1A adrenoceptor partial agonists

Article abstract of DOI:10.1016/j.bmcl.2008.03.070

Novel 2-imidazoles have been identified as potent partial agonists of the α_1A adrenergic receptor, with good selectivity over the α_1B, α_1D and α_2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.

Full text of DOI:10.1016/j.bmcl.2008.03.070

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2930–2934
Novel 2-imidazoles as potent and selective a1A adrenoceptor
partial agonists
Gavin A. Whitlock,a,* Kelly Conlon,b Gordon McMurray,b Lee R. Roberts,a
Alan Stobiea and Richard J. Thurlowb
aDepartment of Chemistry, Pfizer Global Research and Development, Sandwich Labs, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
bDepartment of Genitourinary Biology, Pfizer Global Research and Development, Sandwich Labs, Ramsgate Road, Sandwich,
Kent CT13 9NJ, UK
Received 7 March 2008; revised 25 March 2008; accepted 25 March 2008
Available online 29 March 2008
Abstract—Novel 2-imidazoles have been identified as potent partial agonists of the a1A adrenergic receptor, with good selectivity
over the a1B, a1D and a2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochem-
ical and ADME properties and wide ligand selectivity.
ꢀ 2008 Elsevier Ltd. All rights reserved.
a1-Adrenoceptors are members of the 7TM super family
of G-protein-coupled receptors, and three sub-types of
a1-adrenoceptors have been cloned (a1A, a1B, a1D), ex-
pressed and characterized.1 Sub-type selective agonists
of the a1A receptor have been shown to be efficacious
in in vivo models of stress urinary incontinence (SUI).2
However, full a1A agonists possess a narrow therapeutic
index over a1A mediated cardiovascular effects.3 Re-
cently, workers at Roche disclosed in vitro, in vivo
and PhIIa clinical data on the a1A partial agonist Ro-
115-1240 (Dabuzalgron) 1, that demonstrated its poten-
tial as a treatment for SUI with minimal effects on car-
diovascular parameters.4 The selectivity of 1 for its
urological endpoint over cardiovascular and other side
effects was postulated, in part, to be due to partial a1A
agonism.5 We now wish to report our own work in the
area of a1A partial agonists for the treatment of SUI.
that (i) imidazoles are hydrolytically stable fragments
and (ii) flanking imidazole nitrogen atoms with a 2-sub-
stituent is a precedented strategy for reducing P450 inhi-
bition.11 Some evidence of 2-linked imidazoles with
adrenergic receptor agonist activity had also been re-
ported, with simple naphthalenes 5 showing weak a1
agonist activity.12 Encouraged by this finding, our strat-
egy focused on inserting the 2-imidazole fragment into a
conformationally constrained template 4 which would
incorporate functional groups, such as sulfonamides,
that were known to confer a1A agonist activity.
The target compounds were synthesized according to the
general route outlined in Scheme 1. Reduction of the
cyclic ketone 6 to benzylic alcohol 7 was followed by
chlorination and cyanide displacement to give the ben-
zylic nitrile 9. The nitrile was then converted to the imi-
no-ether 10 by reaction with ethanol saturated with HCl
gas. Displacement of 10 with a glycine aldehyde equiva-
lent followed by cyclization under acidic conditions
afforded the required imidazoles.13
Compounds 1, A-61603 26 and ABT-866 37 are reported
to be potent and selective a1A agonists (Fig. 1). How-
ever, imidazolines have known hydrolytic stability is-
sues,8 and 4-linked imidazoles can suffer from potent
P450 inhibition.9 To circumvent these issues we decided
to introduce a 2-linked imidazole such aas 4,10 reasoning
When heterocyclic substituents were introduced in the 4-
position, the 4-Br indanyl nitriles 24 were employed as
key intermediates. Palladium mediated cross-coupling
with the required heterocyclic coupling partner (boronic
ester/acid, stannane or cuprate) afforded the desired
intermediates 25. Transformation to final compounds
then followed the same procedure as in previous exam-
ples. Test compounds were assessed in vitro for their
Keywords: a1A Adrenoceptor; Partial agonist; Selectivity; 2-Imidazole;
Drug-like properties.
*
Corresponding author. Tel.: +44 1304 649174; fax: +44 1304
651987; e-mail: gavin.whitlock@pfizer.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.070

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2930–2934
2931
( )n
H/Me
Me
N
EtSO2NH
N
N
N
MeSO2NH
O
MeSO2NH
HO
N
N
H
N
H
N
N
H
N
H
H
R
Cl
5
3
1
2
4
Figure 1.
( )n
( )n
( )n
( )n
R1
R2
R1
R2
R1
R2
R1
R2
(c)
(a)
(b)
OH
O
Cl
CN
8
9
6
7
(d)
( )n
( )n
( )n
R1
R1
R2
R1
R2
NH
OEt
NH
N
(f)
(e)
HN
N
H
R2
10
12-23
11
OEt
EtO
CN
R1
R1
R2
(g)
Br
(d) - (f)
N
CN
N
H
R2
R2
24
25
26-38
Scheme 1. Reagents and conditions: (a) NaBH4, MeOH, 0 ꢁC to rt; (b) SOCl2, CH2Cl2, 0 ꢁC; (c) NaCN, DMSO, rt to 50 ꢁC; (d) saturated HCl/
EtOH, 0 ꢁC; (e) H2NCH2CH(OEt)2, EtOH, rt; (f) aq 2 M HCl, 100 ꢁC; (g) HetB(OH)2, Pd(PPh3)4, PhMe, reflux; or HetZnCl, Pd(PPh3)4, dioxane,
reflux; or HetSnR3 (R = Me or n-Bu), Pd(PPh3)4, CuI, LiCl, dioxane, reflux.
Table 1. In vitro functional a1A, a1B, a1D and a2A agonist activity for compounds 1, 3, 12–23
( )n
R1
N
N
R2
H
a,b
Compound
n
R1
R2
a1AEC50
(nM)
a1A Emax
(%)
a1B EC50
a1D EC50
a2A EC50
b,c
a,b
a,b
(Emax
)
(nM)
(Emax
)
(nM)
(Emax
)
(nM)
1
—
—
1
—
—
H
25d
9
60
96
54
71
87
86
54
79
79
47
59
65
40
24
83
61
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
NT
3
H
12
13
14
15
16
17
17a
17b
18
19
20
21
22
23
H
H
473
385
70
2
H
H
791 (58%)
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
364 (74%)
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
722 (105%)
>10,000
>10,000
NT
1
MeSO2NH
EtSO2NH
n-PrSO2NH
MeSO2NH
MeSO2NH
MeSO2NH
MeNHC(O)
MeO
H
1
H
32
1
H
1340
234
142
2150
2200
32
2
H
>10,000
>10,000
>10,000
4340 (44%)
27 (100%)
327 (89%)
NT
2
H
2
H
1
H
1
H
1
MeO
MeO
Me
Cl
Me
Cl
167
451
33
1
1
MeSO2NH
MeSO2NH
NT
>10,000
2
43
NT denotes not tested.
a See Ref. 14 for description of assay conditions.
b Values are geometric means of at least three experiments.
c See Ref. 15 for description of assay conditions.
d Data on Ro-115-1240 1 are in good agreement with published data (Ref. 5).

2932
G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2930–2934
Table 2. In vitro functional a1A, a1B, a1D and a2A agonist activity for compounds 26–38
R1
N
N
R2
a,b
H
Compound
R1
R2
H
a
(nM)
1AEC50
a1A
Emax (%)
a1BEC50
(Emax
a1DEC50
(Emax
a2AEC50
a,b
a,b
)
b,c
)
(nM)
(nM)
(Emax
)
(nM)
H
N
N
26
52
83
600 (32%)
>10,000
336 (57%)
319 (52%)
>10,000
>10,000
N
27
28
H
H
14
3
84
91
N
H
Me
N
902 (14%)
634 (66%)
>10,000
N
H
N
Me
N
N
29
30
H
H
278
58
12
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>2900
N
Me
Me
N
31
32
33
H
H
H
>1300
1150
19
53
36
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
N
N
2060
4580 (25%)
N
O
34
35
36
H
H
H
170
426
111
63
64
63
>10,000
>10,000
>10,000
1390 (38%)
3190 (27%)
>10,000
>10,000
>10,000
>10,000
N
S
N
O
Me
N
H
N
N
37
38
Cl
Cl
322
78
40
52
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
N
N
H
NT denotes not tested.
a See Ref. 14 for description of assay conditions.
b Values are geometric means of at least three experiments.
c See Ref. 15 for description of assay conditions.

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2930–2934
2933
Table 3. Physicochemical, pharmacological and ADME properties of
23
functional agonist activity at human a1A, a1B, a1D and
a2A receptors (see Tables 1 and 2).14,15
23
Indane 12 and tetrahydronaphthalene 13 demonstrated
weak a1A functional agonism in vitro, however, 12
was more selective over a1B and a1D. Introduction of
the methanesulfonamide in compound 14 led to an
increase in a1A potency. Extension of the sulfonamide
to the ethyl analogue 15 improved potency slightly,
but n-propyl example 16 reduced potency significantly.
Ring size also affected potency, with the tetrahydro-
naphthalene sulfonamide 17 showing threefold weaker
a1A activity than 14. To determine whether the a1A
activity resided in a single enantiomer, analogue 17
was separated into enantiomers 17a and 17b.16 It
was found that enantiomer 17a retained the potency,
Emax and selectivity of the racemic mixture whereas
17b had far weaker activity. Following this result
all further analogues were screened as racemic
mixtures.
clogP
LogD7.4
2.3
1.5
HLM, Cli lL/min/mg
Hheps, Cli lL/min/million cells
CaCO-2 flux, AB/BA
hERG activity
<7
<5
18/19
0% activity @ 10 lM
>50· selectivity against
Cerep/BioprintTM panel
(170 assays across receptor, enzyme all targets
and ion channel targets)
CYP2C9, 2C19, 2D6, 3A4 inhibition
<25% inhibition @ 10 lM
tency and Emax levels. Again, this SAR suggested a
hydrogen-bond donor was important for a1A agonist
potency. We then re-introduced a 5-substituent into
the most promising heterocyclic compounds to deter-
mine if this would reduce a1A Emax, as had been the case
for sulfonamide 23. We were pleased to find that a 5-
chloro group in compounds 37 and 38 reduced a1A Emax
to below that for Ro-115-1240 1, but with a concomitant
decrease in a1A potency. The compound from this series
that had the best combination of potent a1A EC50, low
Emax and good selectivity was analogue 38, however,
this compound was not superior to sulfonamide 23 with
respect to a1A potency.
Replacement of the sulfonamide was then investigated.
Secondary amide 18 was poorly tolerated, indicating
the positioning of H-bond donor and acceptor groups
was important for activity. In contrast, the methoxy
substitution in 19 gave equivalent a1A potency, and be-
gan to confer partial agonism by reducing Emax. How-
ever, this change also conferred poor selectivity over
a2A
.
Compound 23 was then progressed to further screening
to assess its overall drug-like properties, and these data
are summarized in Table 3.
Introduction of a 5-substituent in examples 20–23 gave
interesting and quite different results. In the case of
methoxy examples 20 and 21 there was a decrease in
a
1A potency but Emax also dropped to a level below that
These data showed that 23 had attractive drug-like
properties; combining low lipophilicity, excellent selec-
tivity over the hERG channel and P450 enzymes and
against a wide panel of receptors, enzymes and ion chan-
nels. In addition, 23 had excellent in vitro metabolic sta-
bility combined with good membrane permeability
along with no evidence of P-gp mediated efflux in
CaCO-2 cells.
for Ro-115-1240 1. Unfortunately, the additional methyl
substituent did not improve a2A selectivity. In the case
of sulfonamides 22 and 23 the 5-substituent had the
opposite effect, and increased a1A potency. Emax
remained high for compound 22 at 83%, however, the
tetrahydronaphthalene 23 had an attractive pharmaco-
logical profile, combining excellent potency, low Emax
and good selectivity.
In summary we have discovered a novel series of 2-
substituted imidazole a1A adrenoceptor partial agonists
with excellent selectivity over a1B, a1D and a2A. In par-
ticular, sulfonamide 23 and pyrazole 38 were identified
as having the best balance of pharmacological proper-
ties. This work also demonstrated the use of heterocycles
with hydrogen-bond donors as effective bioisosteric
replacements of sulfonamides. Additional screening
highlighted the attractive drug-like properties of sulfon-
amide 23. Further advances in the SAR of this series
along with in vivo efficacy and pharmacokinetic data
will be reported in the near future.
From this investigation we concluded that a sulfon-
amide N–H coupled with a small lipophilic group in
the 5-position was crucial for tuning potency, Emax
and selectivity. To test this hypothesis further, we then
investigated additional replacements for the sulfon-
amide. We reasoned that polar heterocyclic substitu-
ents may act as effective sulfonamide bioisosteres.17
A series of compounds was then synthesized, with
a focus on the indane template for synthetic
expedience.
Heterocycles which included a hydrogen-bond donor,
exemplified by pyrazoles 26, 27 and 28, retained potent
a1A agonism, however, the 2-linked isomer 26 had
poorer selectivity than 27 or 28. Removal of the hydro-
gen-bond donor by N-methylation in examples 29, 30
and 31 led to a significant loss of a1A agonist activity.
Further five and six-membered heterocycles 32–36,
which just contained hydrogen-bond acceptors, were
also investigated but did not deliver the required a1A po-
Acknowledgments
We thank Alison Bridgeland for screening data; Debbie
Lovering, Edward Pegden, Danny Ho, Katherine Eng-
land and Helen Mason for compound synthesis. We also
thank Peter Bungay for ADME assessment of com-
pound 23.

2934
G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2930–2934
12. (a) Amemiya, Y.; Venkataraman, B. V.; Patil, P. N.;
References and notes
Shams, G.; Romstedt, K. Egypt. J. Pharm. Sci. 1994, 35,
403; (b) Amemiya, Y.; Hong, S. S.; Venkataraman, B. V.;
Patil, P. N.; Shams, G.; Romstedt, K.; Feller, D. R.; Hsu,
F. L.; Miller, D. D. J. Med. Chem. 1992, 35, 750.
13. Imidazole final compounds were screened as racemic
mixtures apart from example 17, which was sepa-
rated into single enantiomers by chiral preparative
HPLC.
14. Human a1A (clone 54), a1B (SNB0000700, clone 11) and
a1D (SNB0000706, clone 23) were expressed in Chinese
Hamster Ovary cells. Receptor activation was deter-
mined via calcium mobilization through the Gq pathway
using calcium-sensitive fluorescent dyes (Molecular
Devices, part number R8033), measured by a Fluores-
cent Light Imaging Plate Reader (FLIPr). 11 Point
concentration response curves were calculated, with Emax
calculated as a percent relative to 10 lM phenylephrine
response.
1. (a) Hieble, J. P.; Bylund, D. B.; Clarke, D. E.; Eikenburg,
D. C.; Langer, S. Z.; Lefzowitz, R. J.; Minneman, K. P.;
Ruffolo, R. R., Jr. Pharmacol. Rev. 1995, 47, 267; (b)
Zhong, H.; Minneman, K. P. Eur. J. Pharmacol. 1999,
375, 261.
2. (a) Taniguchi, N.; Hamada, K.; Ogasawara, K.; Ukai, Y.;
Yoshikuni, Y.; Kimura, K. Eur. J. Pharmacol. 1996, 318,
117; (b) Brune, M. E.; O’Neill, A. B.; Gauvin, D. M.;
Katwala, S. P.; Altenbach, R. J.; Brioni, J. D.; Hancock,
A. A.; Sullivan, J. P. J. Urol. 2001, 166, 1555.
3. Carroll, W. A.; Altenbach, R. J.; Buckner, S. A.; Brioni, J.
D.; Brune, M. E.; Kolasa, T.; Meyer, M. D.; Sullivan, J. P.
Med. Chem. Res. 2004, 13, 134.
4. Sorbera, L. A.; Castaner, J. Drugs Future 2004, 29, 216.
5. Blue, D. R.; Daniels, D. V.; Gever, J. R.; Jett, M. F.;
O’Yang, C.; Tang, H. M.; Williams, T. J.; Ford, A. P. D.
W. BJU International 2004, 93, 162.
15. Human a2A (clone SNB0000670) was expressed in Chinese
Hamster Ovary K-1 cells. Receptor activation was deter-
mined via a beta-lactamase reporter gene assay. 11 Point
concentration response curves were calculated, with Emax
calculated as a percent relative to 1 lM dexmeditomidine
response.
6. (a) Knepper, S. M.; Buckner, S. A.; Brune, M. E.;
DeBernadis, J. F.; Meyer, M. D.; Hancock, A. A. J.
Pharmacol. Exp. Ther. 1995, 274, 97; (b) Meyer, M. D.;
Altenbach, R. J.; Hancock, A. A.; Buckner, S. A.;
Knepper, S. M.; Kerwin, J. F., Jr. J. Med. Chem. 1996,
39, 4116.
16. Analogue 17 was separated by chiral HPLC into enanti-
omers 17a and 17b, although absolute stereochemistry was
not determined at this time.
7. (a) Altenbach, R. J.; Khilevich, A.; Meyer, M. D.;
Buckner, S. A.; Milicic, I.; Daza, A. V.; Brune, M. E.;
O’Neill, A. B.; Gauvin, D. M.; Cain, J. C.; Nakane, M.;
Holladay, M. W.; Williams, M.; Brioni, J. D.; Sullivan, J.
P. J. Med. Chem. 2002, 45, 4395; (b) Buckner, S. A.;
Milicic, I.; Daza, A. V.; Meyer, M. D.; Altenbach, R. J.;
Williams, M.; Sullivan, J. P.; Brioni, J. D. Eur. J.
Pharmacol. 2002, 449, 159.
8. Odink, D. A.; Sue, I.-L.; Visor, G. C. WO Patent 02/
38133, 2002.
9. (a) Rodrigues, A. D.; Roberts, E. M. Drug Metab. Dispos.
1997, 25, 651; (b) Testa, B.; Jenner, P. Drug Metab. Rev.
1981, 12, 1.
10. In a recent review of a1-receptor agonists, no 2-imidazoles
were described. Bishop, M. J. Curr. Topics Med. Chem.
2007, 7, 135.
11. For an example where 2-substitution of an imidazole
reduced P450 inhibitory activity, see Tang, C.; Chiba, M.;
Nishime, J.; Hochman, J. H.; Chen, I.; Williams, T. M.;
Lin, J. H. Drug Metab. Dispos. 2000, 28, 680.
17. Heterobiaryl imidazolines with potent a1A agonist activity
have been reported, (a) Bishop, M. J.; Barvian, K. A.;
Berman, J.; Bigham, E. C.; Garrison, D. T.; Gobel, M. J.;
Hodson, S. J.; Irving, P. E.; Liacos, J. A.; Navas, F., III;
Saussy, D. L., Jr.; Speake, J. D. Bioorg. Med. Chem. Lett.
2002, 12, 471; (b) Navas, F., III; Bishop, M. J.; Garrison,
D. T.; Hodson, S. J.; Speake, J. D.; Bigham, E. C.;
Drewry, D. H.; Saussy, D. L.; Liacos, J. A.; Irving, P. E.;
Gobel, M. J. Bioorg. Med. Chem. Lett. 2002, 12, 575; (c)
Hodson, S. J.; Bigham, E. C.; Garrison, D. T.; Gobel, M.
J.; Irving, P. E.; Liacos, J. A.; Navas, F., III; Saussy, D.
L., Jr.; Sherman, B. W.; Speake, J. D.; Bishop, M. J.
Bioorg. Med. Chem. Lett. 2002, 12, 3449; (d) Speake, J. D.;
Navas, F., III; Bishop, M. J.; Garrison, D. T.; Bigham, E.
C.; Hodson, S. J.; Saussy, D. L.; Liacos, J. A.; Irving, P.
E.; Sherman, B. W. Bioorg. Med. Chem. Lett. 2003, 13,
1183.