474
M. J. Bishop et al. / Bioorg. Med. Chem. Lett. 12 (2002) 471–475
pounds with a1A selectivity (27–30). The role of increased
steric bulk [on the 20-substituent of the 2-(phenoxy-
methyl)imidazolines] on subtype selectivity is clearly
exemplified in the selectivity improvement seen by
adding a methyl group to thiazole 24 (compound 24 is
ꢀ10-fold selective vs a1B and a1D while methylthiazole
27 is >2000-fold selective).
Conclusions
A number of novel a1 agonists have been identified in
the 20-heteroaryl-2-(phenoxymethyl)imidazoline series,
including some compounds with sub-nanomolar agonist
potencies at the cloned human a1A-adrenoceptor (19
and 20). Several compounds in the series displayed
agonist subtype selectivity for the cloned human a1A
-
Consistent with literature reports and receptor theory,
the a1A subtype selectivity observed in the cell-based
agonist functional assays did not correlate directly with
subtype selectivity in receptor binding assays, as illu-
strated by the affinity data for selected 20-heteroaryl-2-
(phenoxymethyl)imidazolines shown in Table 2.22
adrenoceptor, with compounds 7, 25, 26, 27, 29 and 30
exhibiting greater than 1000-fold selectivity versus the
cloned human a1B- and a1D-adrenoceptors in our func-
tional agonism assay. These selective a1A-adrenoceptor
agonists are useful tools to test the relationship between
a1A-subtype selectivity and uroselectivity in animal
models.
Table 1. In vitro functional agonism activitya
References and Notes
R
a1A
a1B
a1D
1. (a) The pharmacologically-defined native a1-adrenoceptors
are identified as a1A, a1B and a1D. The corresponding subtypes
characterized by molecular cloning techniques are designated
as a1a, a1b and a1d. For a brief review of a1-adrenoceptor
molecular pharmacology and a recentdiscussion of adreno-
ceptor classification, see: Zhong, H.; Minneman, K. P. Eur. J.
Pharmacol. 1999, 375, 261. (b) Guarino, R. D.; Perez, D. M.;
Piascik, M. T. Cell. Signal. 1996, 8, 323. (c) Hieble, J. P.
Pharm. Acta Helv. 2000, 74, 163. (d) Alexander, S.; Peters, J.;
Mead, A. Trends Pharmacol. Sci. 1998, Suppl, 1.
2. (a) Hieble, J. P.; Ruffolo, R. R., Jr. Drugs Pharm. Sci. 1998,
89, 231. (b) Ruffolo, R. R., Jr.; Hieble, J. P. Eur. Urol. 1999,
36 (Suppl. 1), 17.
3. For a review, see: Haab, F.; Zimmern, P. E.; Leach, G. E.
J. Urol. 1996, 156, 3.
pEC50 %Maxb pEC50 %Maxb pEC50 %Maxb
1 (NS-49)
2
3
4 (cirazoline)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
6.5
7.5
<5.3
7.9
8.5
8.1
7.9
8.7
<4.0
<4.0
<4.0
6.9
5.9
8.6
<4.0
8.9
9.0
8.9
9.3
9.6
8.3
8.3
7.0
8.6
8.5
7.6
7.6
86
105
—
93
96
101
104
109
—
—
—
80
90
97
—
106
101
99
104
98
<4.0
5.7
<5.3
7.2
—
32
—
72
—
—
—
111
—
—
—
—
—
46
—
110
112
104
111
103
39
56
—
100
—
<4.0
<5.3
<5.3
6.9
<4.0
6.1
—
—
—
31
—
20
—
38
—
—
—
—
—
—
—
—
93
111
126
120
—
82
—
113
—
—
—
—
—
—
<4.0
<4.0
<4.0
7.1
<4.0
<4.0
<4.0
<4.0
<4.0
6.2
<4.0
8.0
8.4
9.0
8.3
7.8
7.1
7.9
<4.0
7.7
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
6.8
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
7.8
8.2
8.3
7.9
<4.0
7.6
4. (a) Jonas, D. J. Urol. 1977, 118, 980. (b) Obrink, A.;
Bunne, G. Scand. J. Urol. Nephrol. 1978, 12, 205. (c) Wein,
A. J. Seminars in Urology 1989, 7, 59.
5. (a) Alberts, P.; Bergstrom, P. A. C.; Fredrickson, M. G.
Eur. J. Pharmacol. 1999, 371, 31. (b) Taniguchi, N.; Ukai, Y.;
Tanaka, T.; Yano, J.; Kimura, K.; Moriyama, N.; Kawabe, K.
Naunyn-Schmiedeberg’s Arch. Pharmacol. 1997, 355, 412.
However, recent data suggest that a putative fourth a1 receptor,
the a1L, may play an important role in adrenoceptor mediated
contractions in human urethral tissue. (c) Nishimatsu, H.;
Moriyama, N.; Hamada, K.; Ukai, Y.; Yamazaki, S.;
Kameyama, S.; Konno, N.; Ishida, Y.; Ishii, Y.; Murayama,
T.; Kitamura, T. BJU Int. 1999, 84, 515.
6. (a) Chess-Williams, R.; Chapple, C. CPNS Invest. Drugs
1999, 1, 221. (b) Taniguchi, N.; Hamada, K.; Ogasawara, T.;
Ukai, Y.; Yoshikuni, Y.; Kimura, K. Eur. J. Pharmacol. 1996,
318, 117. (c) Modiri, A.-R.; Fredrickson, M. G.; Gillberg, P.-
G.; Alberts, P. Scand. J. Urol. Nephrol. 2000, 34, 151.
7. Bigham, E. C.; Bishop, M. J.; Drewry, D. H.; Garrison, D.
T.; Hodson, S. J.; Navas, F.; Speake, J. D. PCT Int. Appl.
WO 0066563 A1, 2000; Chem. Abstr. 133, 350215.
8. Bishop, M. J.; Berman, J.; Bigham, E. C.; Garrison, D. T.;
Gobel, M. J.; Hodson, S. J.; Irving, P. E.; Liacos, J. A.;
Minick, D. J.; Navas, F.; Saussy, D. L., Jr.; Speake, J. D.
Bioorg. Med. Chem. Lett. 2001, 11, 2871.
9. (a) Najer, H.; Giudicelli, J. F. Ger. Offen. 1973, DE
2234714. (b) Van Meel, J. C. A.; De Jonge, A.; Timmermans,
P. B. M. W. M.; Van Zwieten, P. A. J. Pharmacol. Exp. Ther.
1981, 219, 235.
119
99
122
102
99
97
104
75
<4.0
7.5
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
—
—
—
—
6.8
7.9
7.4
104
107
—
aSee ref 20 for a description of the assay. Each entry represents the
mean of at least two experiments, with pEC50s having an average SEM
of ꢁ0.11.
b% of phenylephrine response (40 mM).
Table 2. Binding affinities for selected phenoxymethylimidazolinesa
a1A
a1B
a1D
pIC50 (ꢁSEM)b
pIC50 (ꢁSEM)
pIC50 (ꢁSEM)
5
7
8
11
18
25
7.56 (ꢁ0.03)
6.94 (ꢁ0.01)
7.30 (ꢁ0.03)
5.89 (ꢁ0.07)
7.49 (ꢁ0.06)
7.46 (ꢁ0.08)
6.13 (ꢁ0.03)
5.69 (ꢁ0.02)
5.89 (ꢁ0.06)
5.61 (ꢁ0.09)
6.57 (ꢁ0.01)
6.11 (ꢁ0.01)
6.49 (ꢁ0.02)
5.95 (ꢁ0.07)
6.59 (ꢁ0.01)
5.85 (ꢁ0.11)
7.27 (ꢁ0.10)
6.38 (ꢁ0.02)
10. 20-Phenyl-2-(phenoxymethyl)imidazoline is not a novel
compound; see: Pigini, M.; Bousquet, P.; Brasili, L.; Carrieri,
A.; Cavagna, R.; Dontenwill, M.; Gentili, F.; Gianella, M.;
Leonetti, F.; Piergentili, A.; Quaglia, W.; Carotti, A. Bioorg.
Med. Chem. 1998, 6, 2245.
aSee ref 21 for a description of the assay.
bEach entry is the mean of at least two experiments.