2-(anilinomethyl)imidazolines as alpha1A adrenergic receptor agonists: 2'-heteroaryl and 2'-oxime ether series.

Article abstract of DOI:10.1016/S0960-894X(01)00822-8

A series of 2'-heteroaryl and 2'-oxime anilinomethylimidazolines was prepared and evaluated in in vitro functional assays for cloned human alpha1A, alpha1B, and alpha1D receptor subtypes. Potent and selective alpha1A agonists have been identified in these series.

Full text of DOI:10.1016/S0960-894X(01)00822-8

Bioorganic & Medicinal Chemistry Letters 12 (2002) 575–579
2-(Anilinomethyl)imidazolines as ꢀ1A Adrenergic Receptor
Agonists: 20-Heteroaryl and 20-Oxime Ether Series
Frank Navas, III,a,* Michael J. Bishop,a Deanna T. Garrison,a Stephen J. Hodson,a
Jason D. Speake,a Eric C. Bigham,a David H. Drewry,a David L. Saussy,b
James H. Liacos,b Paul E. Irvingb and M. Jeffrey Gobelb
aDivision of Chemistry, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
bDivision of Pharmacology and Molecular Therapeutics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
Received 27 September 2001; accepted 26 November 2001
Abstract—A series of 20-heteroaryl and 20-oxime anilinomethylimidazolines was prepared and evaluated in in vitro functional assays
for cloned human a1A, a1B, and a1D receptor subtypes. Potent and selective a1A agonists have been identified in these series. # 2002
Elsevier Science Ltd. All rights reserved.
Alpha1 adrenergic receptors have an important physi-
ological role in the cardiovascular and urogenital sys-
that it was a potent full agonist at all three subtypes: a1A
(pEC50=9.1); a1B (pEC50=9.4); a1D (pEC50=9.3).
tems.1ꢀ3 Three a1 adrenergic receptor subtypes (i.e., a1A
,
a
1B, and a1D) have been confirmed via cloningtech-
Efforts to develop a selective a1A agonist focused on the
replacement of the methyl ester. Heterocycles17ꢀ23 and
oxime ethers24ꢀ27 have been used as ester bioisosteres.
Isosteric replacement of the methyl ester with a variety
of heterocycles and oxime ethers resulted in the dis-
covery of a1A agonists that are both potent and selec-
tive. The preparation and biological activity of a series of
20-heteroaryl and 20-oxime ethers of 2-(anilinomethyl)-
imidazolines are described herein.
niques.4ꢀ9 The expression levels of these subtypes varies
in different tissues; therefore, development of subtype
specific ligands may result in drugs with improved ther-
apeutic profiles.10 For example, the selective a1A
antagonist tamsulosin has been shown to have fewer
side effects in the treatment of benign prostatic hyper-
plasia than the non-selective a1 antagonist ter-
azosin.11,12 Similarly, the selective a1A agonist NS-49
may be effective in the treatment of stress urinary
incontinence with a lower potential for systemic blood
pressure effects.13,14 The improved therapeutic profile of
NS-49 is due to the predominance of the a1A subtype in
urethal smooth muscle. We are interested in evaluating
selective a1A agonists as potential therapeutic agents for
the treatment of stress urinary incontinence.
The 20-substituted 2-(anilinomethyl)imidazolines were
prepared accordingto the general synthetic scheme illu-
strated in Scheme 1.
The requisite nitro intermediates were prepared by a variety
of synthetic methods. 2-(2-Nitrophenyl)oxazole,28,29
3-methyl-5-(2-nitrophenyl)isoxazole,30 5-(2-nitrophenyl)-
isoxazole,31 and 4-(2-nitrophenyl)isoxazole31 were prepared
20-Carboxylic acid and methyl ester 2-(anilinomethyl)-
imidazolines were reported to be potent pressor agents
and believed to be actingthrough a1 adrenergic activa-
tion.15 Our evaluation of a 20-methyl ester (Fig. 1) at the
three cloned human a1 adrenergic receptors16 revealed
*Correspondingauthor. Tel.: +1-919-483-8066; fax: +1-919-315-
5668; e-mail: fn28689@gsk.com
Figure 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00822-8

576
F. Navas, III et al. / Bioorg. Med. Chem. Lett. 12 (2002) 575–579
Scheme 1.
accordingto literature procedures. The nitro intermediate
for compound 21 was prepared by a method analogous
to that described for 5-(2-nitrophenyl)isoxazole in which
guanidine hydrochloride was used in the presence of
catalytic NaOH to form the 2-aminopyrimidine ring.
The nitro intermediates for compounds 12–13, 17, and
19 were prepared under Ullmann cross-couplingcondi-
tions using2-bromonitrobenzene and the corresponding
bromo- or iodo-substituted heterocycles.32 2-(2-Nitro-
phenyl)furan was prepared by Stille33 couplingof 2-
nitrobromobenzene and 2-tributylstannylfuran in DMF
with tetrakis(triphenylphosphine)palladium as a cata-
lyst. The analogous thiophene intermediate was
obtained in a similar manner using2-nitroiodobenzene,
2-tributylstannylthiophene, and dichlorobis(triphenylphos-
phine)palladium (II) as a catalyst. The nitro inter-
mediates for oxadiazoles 14 and 15 were prepared
accordingto the general procedures described by Orlek
and co-workers.17 4-Methyl-5-(2-nitrophenyl)oxazole
was prepared from 2-nitrobenzaldehyde and 1-(toluene-
4-sulfonyl)ethyl isocyanide34 usingthe egneral proce-
dure described by Possel et al.35 The nitro intermediate
for oxazole 6 was prepared from 2-bromo-20-nitroace-
tophenone usingpotassium acetate and acetic acid fol-
lowed by ammonium acetate and acetic acid under
refluxingconditions. 2-Methyl-4-(2-nitrophenyl)thiazole
was prepared from 2-bromo-20-nitroacetophenone and
thioacetamide. Treatment of 2-bromo-20-nitroacetophe-
none with tetrabutylammonium azide in acetonitrile
between 0 and 25 ꢁC followed by treatment of the
resultant azide with polymer-bound triphenylphosphine
and acetyl chloride in toluene at room temperature gave
the nitro intermediate for methyloxazole 3. The reaction
of 2-nitrobenzaldehyde with methoxylamine hydrochlo-
ride in refluxingEtOH agve the desired nitro inter-
mediate for oxime 26.
provided the majority of desired anilines. The nitro
groups of the isoxazole intermediates were reduced with
stannous chloride and HCl.31 2-(2-Nitrophenyl)furan
and 2-(2-nitrophenyl)pyridine were reduced with 35%
hydrazine in EtOH in the presence of 10% Pd/C. The
nitro intermediates for oxadiazoles 14 and 15 and oxime
26 were reduced with sodium sulfide usingthe general
conditions described by Lin and Lang.36 Commercially
available 5-(2-nitrophenyl)furfural was reduced by the
general method described by Kano and co-workers
usingtitanium (IV) chloride and sodium borohydride to
give the desired aniline intermediate for compound 16.37
4-(2-Nitrophenyl)-2-methylthiazole was reduced by cat-
alytic hydrogenation with platinum oxide in ethanol.
Catalytic hydrogenation of 2-(2-nitrophenyl)thiophene
was carried out in ethanol and acetic acid using10%
palladium on carbon to give the desired aniline. The
remainingnitro intermediates for compounds 1, 3, 6–7,
10, 12–13, 19, 21, and 26 were reduced by catalytic
hydrogenation using 10% Pd/C in EtOH.
The remaininganiline intermediates were prepared by a
variety of synthetic methods as described below. Stille
couplingof 2-chloropyrazine and (2-trimethylstannyl-
phenyl-carbamic acid tert-butyl ester38 with tetra-
kis(triphenylphosphine)palladium (0) in the presence of
catalytic copper (I) bromide followed by deprotection
with trifluoroacetic acid provided 2-(2-aminophenyl)-
pyrazine en route to 18. Suzuki couplingof [2-( N-t-boc-
amino)phenyl]boronic acid with 2-bromo-3-methylpyr-
idine and 2-bromo-3-trifluoromethylpyridine according
to the general procedure described by Snieckus39 fol-
lowed by N-deprotection with trifluoroacetic acid pro-
vided the aniline intermediates for compounds 20 and
22, respectively. Finally, the aniline intermediates for
oximes 23–25 and 27 were prepared by treatment of the
correspondinganilino ketones with the O-alkyl hydrox-
ylamine hydrochlorides in EtOH under refluxingcondi-
tions. The requisite anilino ketones for compounds 25
Reduction of the previously described nitro intermediates
as well as commercially available 5-(2-nitrophenyl)oxazole

F. Navas, III et al. / Bioorg. Med. Chem. Lett. 12 (2002) 575–579
577
and 27 were obtained via Grignard reaction between
anthranilonitrile and ethylmagnesium chloride followed
by hydrolysis with sulfuric acid. The anilino ketones for
compounds 23 and 24 were commercially available.
whereas isoxazole 11 is a less potent but selective a1A
agonist. A similar comparison can be made for oxazoles
10 and 1, respectively. Heteroatom substitution may also
influence activity at the three receptor subtypes. For
example, oxazole 1 was a moderately potent and selec-
tive a1A agonist that was inactive at the a1B and a1D
subtypes. However, replacement of the oxazole nitrogen
with a carbon resulted in a compound (i.e., furan 2) that
was significantly more potent at all three receptor sub-
types and fully efficacious at a1B and a1D. While pyri-
dine 17 and pyrazine 18 are both potent full agonists at
the a1A receptor, the presence of the second nitrogen in
the pyrazine ringresulted in a significant loss of potency
and efficacy at the a1B receptor. Finally, a comparison
between thiophene 12 and furan 16 reveals that sub-
stitution of oxygen for sulfur resulted in an increase in
a1A potency and efficacy. These observations suggest
that the heteroatoms of the 20-aromatic ringcontribute
significantly to the ligand–receptor interactions at all three
receptor subtypes. These heteroatoms (i.e., oxygen and
nitrogen) may act as hydrogen-bond acceptors, which in
turn could either facilitate or inhibit receptor activation.
The anilines described above were coupled to 2-(chloro-
methyl)-2-imidazoline hydrochloride40 as described in
the literature.41,42 All compounds except 3–4, 14–15, 18,
and 23–24 were converted to either their hydrogen
1
chloride or fumarate salts. H NMR and mass spectro-
scopic data were consistent for all final products.
1
Representative H, 13C NMR, and mass spectroscopic
data are provided for compound 20.43
The 20-heteroaryl substituted 2-anilinomethylimidazo-
lines listed in Table 1 range from weak partial agonists
to potent full agonists at the a1A receptor. The a1A
agonists oxymetazoline, naphazoline, and cirazoline are
included for comparison.
Potency and efficacy at the a1A receptor as well as
selectivity versus the a1B and a1D subtypes are influenced
by the heteroatoms of the 20-heteroaromatic ring. The
relative positions of the heteroatoms can significantly
impact potency and selectivity. For example, isoxazole 8
is a potent full agonist at all three receptor subtypes
Substitution of the 20-heteroaryl ringmay also have a
significant effect on subtype potency, efficacy, and
selectivity. The a1B and a1D receptors appear to be
Table 1. In vitro agonist activity of 20-heteroaryl seriesa
pEC50 (% Max. of phenylephrine)b
Compd
W
X
Y
Z
a1A
a1B
<5.3
a1D
<5.3
<5.3
6.9 (31)
<5.30
7.79 (90)
<5.30
<5.30
7.74 (59)
<5.30
<4.00
8.54 (114)
<4.00
8.3 (103)
<4.00
<4.00
7.31 (83)
<5.30
<5.30
<5.70
7.38 (35)
6.74 (38)
7.09 (60)
<4.00
7.54 (44)
<4.00
Oxymetazoline
Naphazoline
Cirazoline
1
2
3
4
5
6
7
7.7 (74)
7.2 (72)
7.9 (93)
<5.3
7.2 (72)
<5.30
8.2 (95)
<5.30
7.16 (21)
8.24 (103)
<5.30
<4.00
8.43 (97)
C
C
C
N
C
C
O
C
O
O
C
C
S
O
N
C
N
N
C
N
C–Me
C
O
C
C
N
C
N
C
C
N
O
C
C
C
C
C
C
C
C–Me
S
C
C–Me
N
N
C–Me
C
O
C–Me
C
C–Me
C–Me
C–Me
C
N
C
O
O
O
C
S
N
C–Me
O
C
N
C
S
C–Me
N
N
O
C
C
N
7.76 (107)
9.33 (101)
6.96 (126)
8.35 (98)
8.65 (99)
6.49 (64)
7.82 (95)
9.10 (134)
7.41 (86)
9.18 (121)
7.34 (99)
7.44 (49)
9.07 (104)
6.18 (92)
6.14 (57)
8.57 (98)
8.17 (103)
8.34 (94)
8.00 (105)
7.61 (104)
7.37 (97)
6.17 (78)
8
9
7.02 (27)
8.79 (123)
10
11
12
13
14
15
16
17
18
19
20
21
22
<4.00
<4.00
6.95 (78)
<5.30
6.17 (43)
7.33 (48)
7.52 (101)
6.47 (48)
7.11 (102)
N
N
C–Me
C
C–CF3
C
N
N
N
<4.00
<5.30
<4.00
N
C
C–NH2
C
aSee ref 16 for description of the assay. Each entry represents the mean of at least two experiments, with an average SEM of ꢂ0.12.
b% of phenylephrine response (40 mM).

578
F. Navas, III et al. / Bioorg. Med. Chem. Lett. 12 (2002) 575–579
Table 2. In vitro agonist activity of 20-oxime seriesa
pEC50 (% Max. of phenylephrine)b
Compd
Isomer
R
R0
a1A
a1B
a1D
23
24
25
26
27
E
E
E
E
Z
CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
H
CH2CH3
7.68 (92)
7.28 (102)
8.48 (112)
7.29 (94)
7.06 (141)
<5.30
<5.30
<4.00
<5.30
<5.30
<5.30
<5.30
<4.00
<5.30
<5.30
aSee ref 16 for description of the assay. Each entry represents the mean of at least two experiments, with an average SEM of ꢂ0.12.
b% of phenylephrine response (40 mM).
Table 3. Comparison of in vitro functional and bindingdata a
increased more than an order of magnitude. In con-
trast, an increase in size of the O-alkyl group resulted
in a slight decrease in potency at the a1A receptor (i.e.,
O-methyl oxime ether 23 vs O-ethyl oxime ether 24).
The effect of configuration about the oxime double
bond on a1A agonist activity was significant. While
both compounds were fully efficacious at the a1A recep-
tor, the (E)-O-methyl oxime ether (25) was more than
25 times as potent as the corresponding Z-isomer (27).
b
Functional assay (pEC50
)
In vitro binding(pIC 50)
Compd
a1A
a1B
a1D
<5.30
<4.00
a1A
a1B
a1D
1
7
8
10
17
19
26
7.76 (107) <5.30
7.82 (95) <4.00
9.10 (134) 8.43 (97)
9.18 (121) 8.79 (123) 8.3 (103)
8.17 (103) 7.52 (101) 7.38 (35)
8.00 (105) 7.11 (102) 7.09 (60)
6.34
6.72
6.64
6.49
6.88
6.35
6.23
5.66
6.79
6.53
6.46
7.42
7.39
6.93
6.38
7.37
8.54 (114) 7.45
7.34
7.09
6.72
6.55
7.29 (94) <5.30
<5.30
While a number of compounds in the 20-heteroaryl and
20-oxime ether series were potent and selective for the
a1A receptor, none were selective for the a1B and a1D
subtypes. This is consistent with the fact that most imi-
dazoline-type a1 adrenergic agonists exhibit some
degree of selectivity for the a1A subtype.44,45 Further-
more, the functional activity observed at the three
receptor subtypes did not generally correlate with their
aSee refs 16 and 46 for descriptions of the assays. Each entry repre-
sents the mean of at least two experiments, with an average SEM of
ꢂ0.12 for the functional assay and ꢂ0.11 for the bindingassay.
b% of phenylephrine response (40 mM).
less able to accommodate substitution of the 20-het-
eroaromatic ring. For example, methyl substitutions
of thiophene 5, furan 2, isoxazole 8, and pyridine 17
to give compounds 12, 16, 9, and 20, respectively,
result in a greater loss of potency and/or efficacy at
the a1B and a1D receptors relative to a1A. In fact, one
may possibly exploit this steric constraint of the a1B
and a1D receptors to design a1A agonists with greater
selectivity.
46
bindingaffinities. For example, oxazoles 1 and 7 were
at least 100-fold more potent at the a1A receptor relative
to a1B and a1D; however, the compounds bound equally
well to all three subtypes (see Table 3). The lack of cor-
relation between the a1 subtype selectivity in the
functional and bindingassays has been attributed to
a difference in intrinsic activity at the three receptor
subtypes.45
Finally, replacement of the methyl group of pyri-
dine 20 with a trifluoromethyl group (i.e., 22) resul-
20-Heteroaryl and 20-oxime anilinomethylimidazolines
have been identified that were potent, selective, and
fully efficacious at the a1A receptor. Functional activity
at the a1A, a1B, and a1D subtypes did not generally cor-
relate with receptor bindingaffinity. In the 2 0-heteroaryl
series, the heteroatoms appeared to play a significant
role in ligand–receptor interactions. Also, the a1B and
a1D receptor subtypes have greater steric constraints in
the vicinity of the heteroaryl ringthan does the a1A
receptor. All of the oxime ethers were fully efficacious at
the a1A receptor and selective. In this series, potency at
the a1A receptor progressively increased as steric bulk at
the oxime carbon was increased. In the case of the O-
methyl propiophenone derivative, the E-isomer was
preferred.
ted in
a loss of potency at the a1A receptor,
suggesting that electron density of the heteroaro-
matic ringmay be important for interaction with
this receptor subtype.
The in vitro a1 functional profiles of the 20-oxime ethers
are listed in Table 2. All of the compounds listed in this
series are selective, full agonists at the a1A receptor
subtype. An increase in steric bulk of the (E)-O-methyl
oxime ethers resulted in an increase in potency at the
a1A receptor. Thus, as size increased from the formyl
(26) to the acetophenone (23) and finally the propio-
phenone derivative (25), potency at the a1A receptor

F. Navas, III et al. / Bioorg. Med. Chem. Lett. 12 (2002) 575–579
579
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pyridinyl)aniline fumarate: H NMR (400 MHz; DMSO-d6) d
2.12 (s, 3H), 3.67 (s, 4H), 4.12 (d, J=5.8 Hz, 2H), 5.53 (br d,
J=6.0 Hz, 1H), 6.38 (s, 2H), 6.66 (d, J=8.2 Hz, 1H), 6.72 (t,
J=7.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 7.21 (t, J=7.6 Hz,
1H), 7.25 (m, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.42 (d, J=4.3 Hz,
1H); 13C NMR (100 MHz; DMSO-d6) d 19.76, 40.65, 45.84,
111.82, 117.79, 123.10, 126.46, 129.81, 130.68, 132.78, 135.84,
139.48, 145.36, 147.30, 157.24, 168.55, 170.61. HRESI-MS:
[M+H]+ 267.1610, found 267.1599.
44. Minneman, K. P.; Theroux, T. L.; Hollinger, S.; Han, C.;
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21. Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.;
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46. Affinity of compounds at a1 adrenoceptor subtypes was
determined by radioligand binding techniques using mem-
branes prepared from Rat-1 fibroblasts expressinghuman a1A
1B, or a1D adrenoceptors as previously described: Gobel, J.;
Saussy, D. L.; Goetz, A. S. J. Pharmacol. Toxicol. 1999, 42, 237.
,
a