Heterocyclic acetamide and benzamide derivatives as potent and selective β3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles

Article abstract of DOI:10.1016/j.bmcl.2010.01.130

A series of amide derived β₃-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation β₃-AR agonists for the treatment of overactive bladder.

Full text of DOI:10.1016/j.bmcl.2010.01.130

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1895–1899
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Heterocyclic acetamide and benzamide derivatives as potent and selective
b3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles
*
Stephen D. Goble , Liping Wang, K. Lulu Howell, Alka Bansal, Richard Berger, Linda Brockunier,
Jerry DiSalvo, Scott Feighner, Bart Harper, Jiafang He, Amanda Hurley, Donna Hreniuk, Emma Parmee,
Michael Robbins, Gino Salituro, Anthony Sanfiz, Eric Streckfuss, Eloisa Watkins, Ann E. Weber,
Mary Struthers, Scott D. Edmondson
Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of amide derived b3-adrenergic receptor (AR) agonists is described. The discovery and optimiza-
tion of several series of compounds derived from 1, is used to lay the SAR foundation for second gener-
ation b3-AR agonists for the treatment of overactive bladder.
Received 7 December 2009
Revised 26 January 2010
Accepted 28 January 2010
Available online 4 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b3 Adrenergic receptor agonist
Overactive bladder
The b3-adrenergic receptor (b3-AR) was discovered in the early
1980s1 and is expressed in a variety of human tissues including
adipose, bladder detrusor, the heart, and the colon.2 As a result,
the b3-AR has been a drug target for several disease areas including
obesity, diabetes, IBS, and overactive bladder (OAB).3
L-796568 (1), developed in the late 1990s for the treatment of
obesity, is a potent and selective agonist of the b3-AR.4 Consistent
with many compounds of this ethanolamine class, 1 possesses low
oral bioavailability in preclinical species.5 Recently, mirabegron (2)
achieved proof-of-concept in humans for the treatment of overac-
tive bladder (OAB), and is currently in Phase III clinical trials.6
In our efforts to address some of the liabilities associated with
these first generation b3-AR agonists, a series of sulfonamide
replacements for 1 were evaluated. A library of over 500 amides
was synthesized in an effort to optimize human b3-AR agonist po-
tency, selectivity over b1-AR and b2-AR, and rodent pharmacoki-
netics in a short period of time.
A library of anilides was synthesized, according to Scheme 1,
from intermediate 3,7 to explore the SAR of the right side of the
molecule. Several analogs of 4 from this library are highlighted in
Table 1. Compound 17 showed excellent potency and good selec-
tivity, but general concerns for potential mutagenicity of aminoh-
eteroaromatic groups8 led to efforts to avoid the aminothiazole
moiety. Thiazole 16, benzopyrazole 11, and benzotriazole 12
showed good functional activity without this potentially muta-
genic functionality. Benzimidazole 8 also showed excellent po-
tency, but possessed no oral bioavailability in rodents. Phenyl
pyrimidinones 24 and 26 also demonstrate excellent b3-AR po-
tency, but possess no oral bioavailability. A comparison of the het-
erocyclic acetamides revealed that the pyrazole and thiazole
offered the most promise for further optimization. In addition,
benzamides such as 5 proved to be another potentially interesting
lead class. Each of these series was further optimized.
The acetamide linker displayed the best b3-AR agonist activity
with heterocyclic substitution in the initial screens, consistent
with a recent report from Astellas (Fig. 1).12 An examination of
acetamide SAR using the benzimidazole moiety as the heterocycle
substituent revealed that a methylene linker was optimal (Table 2).
Heterocycles directly linked to the carbonyl group (27) or with ex-
tended tethers (28 and 30) showed decreased b3-AR potency rela-
tive to the methylene linker (8). In addition, carbamate 29 showed
inferior activity relative to the amide linkers of similar tether
length. Based on these results, acetamide linkers were selected
for further analog optimization.
The SAR of pyrazole acetamide analogs of 4 is summarized in Ta-
ble 3. All benzopyrazoles (10, 11), although potent and selective over
b1- and b2-ARs, possess low (<5%) oral bioavailability. Removal of the
fused phenyl ring (33) led to decreased b3-AR agonist potency. The
addition of phenyl groups at the 4 and 5 positions of the pyrazole
ring increased potency (32 and 36). The addition of a methyl group
to the 3 position also improved b3-AR potency (34). Dimethyl analog
35 was both active and selective over b1-AR and b2-AR. This analog
also possesses improved oral bioavailability in rats (43%).
* Corresponding author. Tel.: +1 732 594 7160; fax: +1 732 594 9473.
E-mail address: stephen_goble@merck.com (S.D. Goble).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.130

1896
S. D. Goble et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1895–1899
1. RCO2H, EDC
OH
OH
H
Boc
N
HOAT or RCOCl
N
Et3N, DCM
O
4
N
H
R
2. HCl/dioxane
N
NH2
N
3
Scheme 1. Synthesis of analogs 4.
Table 1
Comparison of b3-AR agonist activity and b1-AR and b2-AR binding affinity for anilide analogs of 4 and 19
N
21
22
R = Ph
R = Me
5
12
N
H
N
R
N
O
N
N
N
6
7
13
14
Ph
N
23
24
N
O
N
N
N
H
N
8
9
N
N
N
N
N
O
N
15
N
NH2
N
25
26
R
R
N
N
H
O
16
R=Me
17 R=NH2
S
10
11
R=Ph
18
N
N
N
S
N
S
Me
19
20
R=Me
R=Ph
N
N
N
Me
O
10
11
11
Compound
b3 Agonist activity EC50 nM (% act)
b1 Binding affinity IC50
,
lM
b2 Binding affinity IC50 , lM
1
5
6
7
8
3.6 (94)
297 (40)
95 (61)
225 (34)
8.8 (48)
19 (94)
48 (97)
14 (67)
24 (73)
21 (70)
693 (81)
22 (111)
103 (87)
6.8 (75)
174 (75)
74 (92)
86 (73)
8.0 (98)
171 (78)
64 (77)
19 (96)
19 (103)
16 (75)
2.3
2.3
>20
>20
3.0
>10
9.6
19
3.1
7.6
0.6
>20
>20
>10
8.3
1.5
>10
1.1
>10
>20
1.4
3.4
3.0
3.6
>20
>20
>10
6.0
>10
15
>10
13
1.1
>20
>20
>10
8.7
1.7
>10
1.7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
>10
>20
6.7
>10
>10
7.8
Substitutions
a
to the amide carbonyl in the pyrazole series
tency (41) but N-methyl derivatives of 17 lacked b3-AR agonist
activity (42). Replacement of the aminothiazole with a methyl thi-
azole (16) furnished a compound which retained some potency
and increased oral bioavailability for the first time in this series.
Phenyl substitution (18) showed decreased b1/2-AR selectivity
and no improvement in potency. The addition of a second methyl
group to 16 gave a compound with improved potency, selectivity
and rat PK profile (43).
were next explored. The addition of a methyl group at this position
gave a large boost in potency (37 and 38). Only one diastereomer
showed full b3-AR agonist activity (37) while the other appeared
to be a partial agonist (38).14 The dimethyl analog (39) was signif-
icantly less potent at b3-AR. Methylation
dimethyl pyrazole analog (40) also afforded a loss in potency, indi-
a to the carbonyl of the
cating a possible steric interaction between the
and the pyrazole 2-methyl group.
a-methyl group
Optimization of the benzamide series is described in Table 5.
Ortho substitutions led to compounds with moderate b3-AR agonist
activity (e.g. 44). Meta (45, 57–59) and para (46, 60) substitution,
The optimization of thiazole analogs is shown in Table 4. The
addition of an methyl group to 17 improved b3-AR agonist po-
a

S. D. Goble et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1895–1899
1897
and benzimidazole (55) substitution improved potency but with
a detrimental effect on oral bioavailability in rats. Although
marked by high plasma clearance, simple extended tether substit-
uents (54, 56) also showed good potency but with bioavailabilities
of 9% and 15%, respectively. Extended tethered heterocycles, such
as pyrrole 53, mitigated the high clearance and improved the po-
tency. Simple heterocyclic substitutions not possessing an NH
functionality all showed good potency and PK profiles (47, 48).
Simple pyrrolidine 47 in particular showed b3-AR agonist activity,
lower clearance and improved bioavailability for this series. When
this pyrrolidine benzamide was additionally substituted at the
meta and para positions with a methyl group, compounds with
comparable potency and selectivity and improved oral bioavaila-
bilities were found (61 and 62).
In summary, the synthesis of a library of amides as sulfonamide
replacements on the right side of the ethanolamine core of 1 led to
the discovery of leads in three different classes.15 Pyrazole 37, thia-
zole 43, and benzamides 61 and 62 showed good potency, selectivity
and much improved pharmacokinetic profiles over previous analogs
from the sulfonamide series (e.g., 1). These compounds are the first
b3-AR agonist anilides in this series reported to possess oral bioava-
ilabilities in rats above 20% while possessing good selectivities over
OH
H
N
NH
S O
O
N
N
F3C
S
1
OH
H
N
NH2
S
O
N
N
H
2
Figure 1. Merck’s L-796568 (1) and Astellas’ mirabegron (2).
although showing potent EC50s, led to a loss in receptor activation
and a large increase in binding affinity at b1-AR. Several ortho
substituted benzamides were synthesized in an attempt to opti-
mize this series. Similar to the acetamide series, imidazole (49)
Table 2
Varying tethers and substitution to the benzimidazole9
OH
H
N
O
N
N
N
N
H
X
R
11
11
Compound
X
R
b3 Agonist activity EC5010, nM (% act)
b1 Binding affinity IC50
,
lM
b2 Binding affinity IC50 , lM
27
8
28
29
30
Bond
–CH2–
–(CH2)2–
–OCH2–
–(CH2)2–
H
H
H
H
283 (40)
8.8 (48)
2647 (41)
>10 k (11)
454 (60)
1.1
6.0
>20
>10
>20
8.6
>10
>20
0.84
11
CH3
Table 3
Comparison of b3-AR agonist activity, b1-AR and b2-AR binding affinity, and rat PK profiles for select pyrazole derivatives9
31
37 entA
38 entB
N
N
34
35
N
N
N
N
Ph
N
Ph
32
33
N
39
N
N
N
N
Ph
N
36
N
40
N
N
N
Ph
N
11
Compound
b3 Agonist activity EC5010, nM (% act)
b1/b2 Binding affinity IC50
,
lM
Rat PK
Fa (%)
a
Clp (mL/min/kg)/t1/2 (h)
31
32
33
34
35
36
37
38
39
40
261 (66)
580 (84)
218 (64)
241 (88)
123 (92)
498 (72)
27 (98)
10 (49)
3768 (109)
1404 (50)
0.6/16
—
52/2.7
—
—
46/1.0
—
85/1.6
56/1.9
—
—
22
—
—
43
—
12
26
—
>20/>20
>20/>20
>20/>20
>20/>20
3.6/>20
>20/>20
>20/>20
>20/>20
>20/>20
—
—
a
‘—’ indicates not tested; compounds were dosed as cassette mixtures.13

1898
S. D. Goble et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1895–1899
Table 4
Comparison of b3-AR agonist activity, b1 and b2 binding affinity, and PK profile for select thiazole derivatives9
HO
H
N
R3
S
R2
O
N
N
N
H
R1
R1
R2/R3
b3 Agonist activity EC5010, nM (% act)
b1/b2 Binding affinity IC50
, lM
Rat PK
11
Compound
Fa (%)
a
Clp (mL/min/kg)/t1/2 (h)
16
41
42
43
H
Me
H
H/Me
103 (87)
1.9 (88)
978 (39)
37 (86)
>10/>10
>20/>20
16/0.7
11/1.4
10/20
—
15
0
—
H/NH2
H/NHMe
Me/Me
H
>20/>20
51/1.6
32
a
‘—’ indicates not tested; compounds were dosed as cassette mixtures.13
Table 5
Comparison of b3-AR agonist activity, b1 and b2 binding affinity, and PK profile for select benzamide derivatives9
OH
H
N
R1
O
N
N
H
R3
R2
N
a
b
h
i
S
N
e
f
-(CH2)2Ph
N
H
N
N
N
N
j
c
d
N
N
g
O
-CH2-O-Ph
k
N
H
R1
R2/R3
b3 Agonist activity EC5010, nM (% act)
b1/b2 Binding affinity IC50
, lM
Rat PK
11
Compound
Fa (%)
a
Clp (mL/min/kg)/t1/2 (h)
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
a
H
H
b
c
d
e
f
H/H
a/H
H/a
179 (76)
184 (52)
187 (32)
67 (86)
76.2 (88)
21 (115)
36 (94)
42 (81)
86 (86)
24 (74)
32 (74)
35 (67)
47 (66)
6.9 (21)
10 (21)
37 (21)
105 (30)
73 (77)
76 (97)
>20/13
0.4/4.9
0.06/1.9
5.3/>20
>10/>10
>10/>10
>20/5.0
3.0/6.0
>20/>20
6.9/12
1.7/2.4
>10/1.7
4.7/9.8
0.6/>10
0.4/4.1
0.4/4.0
0.1/1.9
15/12
—
—
—
—
—
—
H/H
H/H
H/H
H/H
H/H
H/H
H/H
H/H
H/H
H/H
n/H
d/H
58/1.3
39/1.6
30/14
143/1.2
158/1.5
—
75/1.6
132/1.4
106/3.2
165/1.7
—
—
—
—
74/1.8
33/2.3
9.6
7.5
0
4.7
7.5
—
6.4
9.2
0
15
—
—
—
—
24
12
g
h
i
j
k
H
H
H
H
b
b
i/H
H/i
Me/H
H/Me
16/19
R1, R2, and R3 are selected from the groups a–k.
a
’—’ indicates not tested; compounds were dosed as cassette mixtures.13
b1-AR and b2-AR (up to 1000-fold). These compounds have provided
leads for further optimization of the ethanolamine core and have
established the SAR foundation for application to a second genera-
tion of b3-AR agonists. Further efforts to incorporate the SAR de-
scribed in this report into new structure classes and further
References and notes
1. Arch, J. R. S. Proc. Nutr. Soc. 1989, 48, 215.
2. Strosberg, A. D. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421.
3. (a) Weber, A. E. Annu. Rep. Med. Chem. 1998, 33, 193; (b) Weyer, C.; Gautier, J. F.;
Danforth, E. Diabetes Metab. 1999, 25, 11; (c) Nomiya, M.; Yamaguchi, O. J. Urol.
2003, 170, 649; (d) Takeda, M.; Obara, K.; Mizusawa, T.; Tomita, Y.; Aria, K.;
Tsutsui, T.; Hatano, A.; Takahashi, K.; Nomura, S. J. Pharmacol. Exp. Ther. 1999,
information of the optimal stereochemical configuration at the
methyl chiral center will be disclosed in future communications.
a-

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288, 1367; (e) Yamaguchi, O.; Chapple, C. R. Neurourol. Urodyn. 2007, 26, 752;
(f) Tanka, N.; Tamai, T.; Mukaiyama, H.; Hirabashi, A.; Muranaka, H.; Ishikawa,
T.; Kobayashi, J.; Akahane, S.; Akahame, M. J. Med. Chem. 2003, 46, 105; (g)
Tyagi, P.; Tyagi, V.; Yoshimura, N.; Chancellor, M.; Yamaguchi, O. Drugs Future
2009, 34, 635; (h) Hieble, P. J. Curr. Top. Med. Chem. 2007, 7, 207.
11. The binding affinity of compounds to the b1-AR and b2-AR receptors was
determined in standard competition binding assay using membranes
a
prepared from recombinant cells expressing either b1-AR or b2-AR (Forrest,
M. J.; Hom, G.; Bach, T.; Candelore, M. R.; Cascieri, M. A.; Strader, C.; Tota, L.;
Fisher, M. H.; Szumiloski, J.; Ok, H. O.; Weber, A. E.; Wyvratt, M.; Vicario, P.;
Marko, O.; Deng, L.; Cioffe, C.; Hegarty-Friscino B.; MacIntyre E. Eur. J.
4. (a) Mathvink, R. J.; Tolman, S. J.; Chitty, D.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, E. D.;
Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 2000,
10, 1971; (b) Mathvink, R. J.; Tolman, S. J.; Chitty, D.; Candelore, M. R.; Cascieri,
M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre,
E. D.; Miller, R. R.; Stearns, R. A.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A.
E. J. Med. Chem. 2000, 43, 3832.
5. For early examples see: Hoffman, C.; Leitz, M. R.; Obendorf-Maass, S.; Lohhse,
M. J.; Klotz, K. N. Naunyn Schmiedebergs Arch. Pharmacol. 2004, 369, 151.
6. Maruyama, T.; Suzuki, T.; Onda, K.; Hayakawa, M.; Moritomo, H.; Kimizuka, T.;
Matsui, T. U.S. Patent 6,346,532, 2002; Chem. Abstr. 1998, 129, 19801.
7. Naylor, E. M.; Colandrea, V. J.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F.;
Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C. D.;
Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fischer, M. J.; Weber, A. E. Bioorg. Med.
Chem. Lett. 1998, 8, 3087.
8. (a) Benigni, R.; Giuliani, A.; Franke, R.; Gruska, A. Chem. Rev. 2000, 100, 3697;
(b) Wang, C.-Y.; Muraoka, K.; Brian, G. T. Cancer Res. 1975, 35, 3611.
9. b3-AR EC50’s and activation and b1-AR and b2-AR binding affinities are generally
reported as means of n P 2, with standard deviations 650% of the mean. The
comparison of b3-AR EC50’s and b1-AR and b2-AR IC50’s is used as an assessment
of selectivity (see Ref. 4a).
10. The ability of compounds to activate the human b3-AR receptor was measured
using a CHO cell line stably expressing the receptor (Naylor, E. M.; Parmee, E.
R.; Colandrea, V. J.; Perkins, L.; Brockunier, L.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F., Jr.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D.
E.; Strader, C. D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E.
Bioorg. Med. Chem. Lett. 1999, 9, 755). The cell line used expressed b3-AR at
levels very similar to those observed in the human bladder detrusor muscle
(unpublished observation). To quantify the amount of cAMP released following
Pharmacol. 2000, 407, 175). WGA-PVT SPA beads (GE Amersham; 150
lg)
were mixed with either 2 g b1-AR or 1 g b2-AR membranes per well of a 384-
l
l
well plate in assay buffer (50 mM Tris, pH 7.4, 5 mM MgCl2, 2 mM EDTA, 3%
glycerol and 0.1% BSA) containing a protease inhibitor cocktail (Sigma #P8340).
Beads and membranes were then allowed to pre-incubate for 20 min at room
temperature. Compounds were next serially diluted in DMSO and an aliquot
added to each well in assay buffer. The reaction was then initiated by the
addition of 125I-cyanopindolol (2200 Ci/mmol; Perkin–Elmer) at
a final
concentration of 40 pM. The assay plates are incubated for 3–4 h at room
temperature and then counted in a Wallac Scintillation Counter (Perkin–
Elmer). Total binding is measured in the absence of compound while maximal
inhibition is determined by the addition of 10 lM (final concentration)
unlabeled cyanopindolol in control wells. All counts are then normalized to
percent inhibition and the IC50 determined using a custom in-house data
analysis package.
12. Maruyama, T.; Onda, K.; Hayakawa, M.; Matsui, T.; Takasu, T.; Ohta, M. Eur. J.
Med. Chem. 2009, 44, 2533.
13. Male Sprague-Dawley rats were dosed with compound in solution
intravenously at 0.5 mg/kg and orally at 1 mg/kg using EtOH:PEG vehicle. In
cassette dosing, four compounds were dosed simultaneously with a control
(For a review on the theory of cassette dosing see: White, R. E.; Manitpisitkul,
P. Drug Metab. Disp. 2001, 29, 957)
14. Experimental procedure for the preparation of 37 and 38: To a stirred, room
temperature mixture of rac-2-(1H-pyrazol-1-yl)propanoic acid (58.8 mg,
0.420 mmol), HOBT (0.769 mL, 0.462 mmol), EDC (80 mg, 0.42 mmol) and
DIEA (0.147 mL, 0.839 mmol) in DMF (3 mL) was added
3 (150 mg,
0.420 mmol, Ref. 7). The reaction mixture was stirred at room temperature
for 18 h then diluted with EtOAc and washed with saturated aqueous sodium
bicarbonate, water and then brine. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The resulting
crude Boc-protected intermediate was dissolved in EtOAc (2 mL) and 2 M HCl
in ether (2 mL) was added. The reaction mixture was stirred at room
temperature for 2 h and concentrated to dryness. The product was purified
by reverse phase HPLC (0.1% NH4OH in H2O/MeCN) to give 132 mg of the free
base mixture of stereoisomers. Separation of the two stereoisomers was
accomplished using SFC (OD-H column, eluting with 20% MeOH w/0.1% Et3N in
CO2 at 50 mL/min (100 bar) to give 38 (33 mg, 0.088 mmol, 21% from 3) as the
first eluting isomer and 37 (45 mg, 0.12 mmol, 29% from 3) as the second
eluting isomer. ESI-MS calculated for C21H25N5O2: 379.20. Found 380.14 (M+H,
b3-AR activation, the LANCE cAMP kit (Perkin–Elmer),
a time-resolved
fluorescence resonance energy transfer immunoassay, was used. Compounds
were serially diluted in DMSO and an aliquot added to either 384-well or 96-
well micro titer plates in assay buffer (5 mM HEPES, 0.1% BSA in Hank’s
Balanced Salt Solution). The reaction was initiated by the addition of 6000 cells
per well in assay buffer that also contained a cAMP specific antibody labeled
with Alexa Fluor 647 and a phosphodiesterase inhibitor (IBMX). Following a
30 min incubation at room temperature, the cells were lysed by the addition of
LANCE detection buffer which contained a europium-labeled cAMP tracer.
Fluorescence was measured following
a one hour incubation at room
temperature using a Perkin–Elmer Envision plate reader, exciting at 340 nm
and measuring emission at 615 nm and 665 nm. For each assay, a cAMP
standard curve was included and used to convert fluorescence readings
directly to cAMP amounts. The values were then normalized to isoproterenol, a
known full agonist of b3-AR, which was titrated in every assay and the EC50
38) and 380.15 (M+H, 37). The absolute stereochemistry of the methyl group
a
to the carbonyl was not determined.
15. (a) For earlier work on anilide series see: Ref. 6.; (b) Weber, A. E.; Parmee, E. R.;
Mathvink, R.; Ashton, W. T.; Naylor, E. M. U.S. Patent 6,291,491, 2001; Chem.
Abstr. 2001, 135, 242138.
determined using a custom in-house data analysis package. Along with EC50
the percent maximum activation relative to isoproterenol is reported.
,