Discovery of 6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a]imidazol-3- ylmethylamines, a novel class of corticotropin-releasing factor receptor type 1 (CRF1R) antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.04.094

A novel series of [6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a] imidazol-3-ylmethyl]-dialkylamines was discovered as potent CRF₁R antagonists. The optimization of binding affinity in the series by the parallel reaction approach is discus

Full text of DOI:10.1016/j.bmcl.2010.04.094

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3669–3674
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a]
imidazol-3-ylmethylamines, a novel class of corticotropin-releasing factor
receptor type 1 (CRF1R) antagonists
*
Dmitry Zuev , Vivekananda M. Vrudhula, Jodi A. Michne, Bireshwar Dasgupta, Sokhom S. Pin,
Xiaohua Stella Huang, Dedong Wu , Qi Gao, Jie Zhang à, Matthew T. Taber,
*
John E. Macor, Gene M. Dubowchik
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of [6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-dialkylam-
ines was discovered as potent CRF1R antagonists. The optimization of binding affinity in the series by
the parallel reaction approach is discussed herein.
Received 8 February 2010
Revised 20 April 2010
Accepted 21 April 2010
Available online 24 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Corticotropin-releasing factor
Depression
Anxiety
Parallel synthesis
Corticotropin-releasing factor (CRF), a 41-amino acid neuropep-
tide produced by hypothalamic nuclei in brain, plays an essential
role in the regulation of the hypothalamic–pituitary–adrenal
(HPA) axis and in the coordination of neuroendocrine, autonomic,
behavioral and immune responses to stress.1,2 The physiological ef-
fects of CRF are mediated through the known CRF1 and CRF2 recep-
tor subtypes, of which the CRF1 receptor is believed to play a
pivotal role in stress-related responses.3 A large body of pre-clini-
cal and clinical data links CRF to psychopathology of a variety of
stress-related dysfunctions, such as anxiety, depression, obses-
sive–compulsive and post-traumatic stress disorders.4–7 It has
been hypothesized that selective CRF1R antagonists may be useful
for the treatment of these illnesses.
A large majority of these compounds contain either bicyclic or
monocyclic core structures. As shown in Figure 1, a typical exam-
ple of the former chemotype 1 consists of a heterobicyclic core,
which possesses a basic sp2-hybridized nitrogen atom, essential
for hydrogen bonding between the receptor and the ligand. At-
tached to the core are a hydrophobic (usually dialkylamino) side
chain R2-Y-R3 and a substituted phenyl or 3-pyridyl ring. The latter
aromatic moiety possesses a 4-positional substituent R5, which
R2, R3 = alkyl or haloalkyl
groups
A number of potent non-peptide CRF1 antagonists have been re-
ported over the past 15 years, reflecting significant efforts of many
research groups in this area.8–10 A thorough analysis of structure–
activity relationships led to the postulation of a general CRF1
antagonist chemotype.8
R3
Y = CH, N
5- or 6- membered rings
R2
Y
R1 = small groups
R
4 = required
R1
N
R7
Y
R4
R5
Z
* Corresponding authors. Tel.: +1 203 677 6714; fax: +1 203 677 7702.
E-mail addresses: dmitry.zuev@bms.com (D. Zuev), gene.dubowchik@bms.com
(G.M. Dubowchik).
R5, R6, R7 = small groups
Y, Z = CH, N
R6
Present address: AstraZeneca PLP, 1800 Concord Pike, Wilmington, DE 19850,
USA.
1
à
Present address: Aventis Pharmaceuticals, PO Box 6800, Bridgewater, NJ 08807-
0800, USA.
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.094

3670
D. Zuev et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3669–3674
R2
Based on these general considerations, we designed imi-
Amine Library: Optimize Activity Based
on Available Amines
dazo[1,2-a]imidazole derivatives 2 as novel CRF1R antagonists
(Fig. 2). Our goal was to develop an efficient synthesis of the het-
erocyclic core of the molecule with a late stage introduction of
diversity elements. The proposed approach would allow us to
effectively optimize the potency of the target compounds by a sys-
tematic modulation of the steric and electronic properties of aryl
rings as well as by the utilization of a wide variety of available
amines.
The synthetic pathway towards imidazo[1,2-a]imidazole deriv-
atives 2 is illustrated in Scheme 1. While methyl imidazole 4a was
commercially available, trifluoromethyl analog 4b was prepared by
condensation of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate 3
with formamide.11 Bromination of 4a and 4b with NBS provided
bromoimidazoles 5a and 5b, which were alkylated with 2-bro-
mo-N-mesitylacetamide12 in the presence of DBU to yield products
6a and 6b. We found that the regioselectivity of N1 versus N3
alkylation of bromoimidazoles 5a and 5b was highly dependent
R3
N
N
R1
R4
R5
Bicyclic Core: Develop Efficient Synthesis
N
N
R7
Aryl Library: Modulate Steric and Electronic
Properties of Aryl Ring
R6
2
Figure 2.
interacts with a hydrophobic pocket of the CRF1 receptor, as well as
2- and/or 6-positional substituents R4 and R6, and is required for
the maintenance of an orthogonal binding conformation.
O
O
H
N
O
O
H
N
H
Br
b
a
O
O
F3C
O
N
N
Cl
R
R
3
4a R = CH3
4b R = CF3
5a R = CH3
5b R = CF3
O
O
N
Br
O
N
H
Br
O
O
c
N
+
N
R
O
HN
N
R
6a R = CH3
6b R = CF3
7a R = CH3
7b R = CF3
O
O
O
O
R
N
N
d
e
R
O
Cl
6a R = CH3
6b R = CF3
N
N
N
N
8a R = CH3
8b R = CF3
9a R = CH3
9b R = CF3
O
N
N
N
N
f
g
R
Cl
R
Cl
N
N
N
N
10a R = CH3
10b R = CF3
11a R = CH3
11b R = CF3
Scheme 1. Reagents and conditions: (a) HCONH2, H2O, 135 °C, 2 h, 24%; (b) NBS, 1,2-dichloroethane, 85 °C, 4 h, 85%; (c) 2-bromo-N-mesitylacetamide, DBU, toluene–acetone,
55 °C, overnight, 88–90%; (d) Ag2CO3 or AgOTf, tetramethylenesulfone, 150 °C, 73%; (e) POCl3, 55 °C, 15 min, 50–80%; (f) Me3Al, N-(cyclopropylmethyl)propan-1-amine,
toluene, reflux, 14 h, 68–100%; (g) Red-Al, toluene, rt, overnight, 64%.

D. Zuev et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3669–3674
3671
Table 1
H3C
N
CH3
N
hCRF1R binding affinities of N,N-disubstituted aminomethylimidazo[1,2-a]imidazoles
11
N
N
R1
N
N
N
R2
Cl
Cl
N
F3C
Cl
12
Figure 3.
N
N
on the nature of the C4-substituent. While the alkylation of methyl
imidazole 5a displayed virtually no stereoselectivity,13 the alkyl-
ation of trifluoromethyl imidazole 5c was completely N1-regio-
specific.14 Silver salt assisted cyclization of 6a and 6b in sulfolane
furnished constrained imidazoles 8a and 8b. Heating of the latter
compounds with phosphorus trichloride at 150 °C in a high-pres-
sure vessel then provided 6-chloroimidazo[1,2-a]imidazoles 9a
and 9b. The trimethylaluminum promoted amidation15 of 9a and
9b with N-(cyclopropylmethyl)propan-1-amine yielded amides
10a and 10b, which were converted to the corresponding amines
11a and 11b by Red-Al reduction16 in toluene.
11
Compd
R1
R2
Ki (nM)
11b
11c
11d
11e
11f
11g
11h
11i
cPrCH2
cPrCH2
cPrCH2
cPrCH2
nPr
nPr
nPr
nPr
nPr
CF3CH2
Et
CF3CH2CH2
CF3CH2
CF3CH2CH2
CH3OCH2CH2
nPr
9.1
5.2
9.0
16
8.3
12
32
69
It soon became evident that the presence of another electron-
withdrawing group at the imidazo[1,2-a]imidazole core was neces-
sary to ensure chemical stability. Indeed, a trifluoroacetate salt of
methyl derivative 11a, upon exposure to acetonitrile, suffered the
loss of its amino side chain, undergoing spontaneous dimeriza-
tion17 to form compound 12 (Fig. 3). In contrast, trifluoromethyl
derivative 11b was chemically stable under the described
conditions.18
We found the Weinreb amidation/Red-Al reduction sequence to
be inconvenient for rapid parallel synthesis of amines 11, due to
the moisture-sensitivity of both reactions and tedious aqueous
work-ups. As an alternative, ester 9b was quantitatively reduced
to alcohol 13 with DIBAL-H, followed by the conversion of the lat-
ter to chloromethyl intermediate 14 by reaction with thionyl
chloride (Scheme 2). Alkylation of both primary and secondary
amines19 with 14 in acetonitrile in the presence of Hünig’s base
cleanly produced the corresponding monoalkylated products with-
out any detectable over alkylation.20 The reaction occurred at room
11j
11k
11l
nPr
nBu
nBu
Allyl
Allyl
Metallyl
cBuCH2
cBuCH2
cBuCH2
cPrCH2CH2
cPrCH2CH2
cPrCH2CH2
cPrCH2CH2
CF3CF2CH2
Et
Me
nPr
Allyl
Et
nPr
CF3CH2
Et
CF3CH2
Et
440
78
310
4.5
13
67
5.3
13
16
6.3
13
53
110
11m
11n
11o
11p
11q
11r
11s
11t
11u
11v
nPr
CF3CH2CH2
temperature and was usually completed within 15 min. For conve-
nience, no aqueous work up was necessary, as the homogeneous
reaction mixture could be directly injected into a reversed phase
preparative HPLC system for purification.21
O
O
HO
N
N
F3C
Cl
F3C
Cl
a
b
N
N
N
N
9c
13
R1
Cl
N
R2
N
N
c
F3C
Cl
F3C
Cl
N
N
N
N
14
11
Scheme 2. Reagents and conditions: (a) DIBAL-H, THF, 0 °C to rt, 2 h, 100%; (b) SOCl2, CH2Cl2, 0 °C, 30 min, 100%; (c) R1R2NH, Et3N, CH3CN, rt, 15 min, 50–95%.

3672
D. Zuev et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3669–3674
The general approach presented in Scheme 2 was successfully
amine 15m. n-Propyl 15q and methyl 15s analogs were, respec-
tively, 3.5 and 25 times less potent than 15r. Pyridyl-containing
derivatives 15t–v were less active than 15s, suggesting that polar
atoms in the side chain are not well-tolerated by the receptor for
this chemotype. Surprisingly, more lipophilic fluoroethyl and flu-
oropropyl analogs 15w and 15x were significantly less potent than
15r and 15q. In the benzylamine series, the introduction of a fluo-
rine atom on the phenyl ring of 15a or 15h did not result in signif-
icant changes in potency for 15b and 15c or 15k and 15l. However,
para-chlorophenyl analogs 15e and 15i were 3.5 and 6 times more
potent than 15a and 15h.
applied to the parallel synthesis of a number of imidazo[1,2-a]imi-
dazoles 11, 15–17 in generally good yields.22 The CRF1R binding
affinities of these analogs were determined by displacement of
[
125I] Tyr-o-CRF from hCRF1R endogenously expressed on IMR-32
human neuroblastoma cells23 and are summarized in Tables 1–4.
Initially, we investigated the effect of the amino side chain on
binding potency of analogs 11 (Table 1). Cyclopropylmethyl
amines 11b–e displayed high binding affinity. While n-propyl
derivatives 11f and 11g were nearly as potent as their cyclopro-
pylmethyl analogs 11c and 11e, replacement of the cyclopropylm-
ethyl group in 11b with n-propyl resulted in almost 7.5-fold loss in
activity for 11i. Terminal trifluorination of the n-propyl side chain
gave a sixfold advantage in potency for 11g over 11i; however, fur-
ther introduction of fluorine atoms (as in 11j) had an unfavorable
effect on binding. Allyl derivative 11m was the most potent com-
pound in the series. The expansion of the cyclopropyl ring in
11b–d to cyclobutyl did not result in a significant change in bind-
ing affinity for 11p–r. However, the effect of homologation of the
cyclopropylmethyl group appeared to be sensitive to the length
of substituent R2. In particular, while trifluoroethyl 11s and ethyl
11t derivatives were equipotent with 11c and 11d, significant loss
in activity was observed for n-propyl 11u and 3,3,3-trifluoropropyl
11v analogs, compared to 11b and 11e.
Table 3
hCRF1R binding affinities of cyclic aminomethylimidazo[1,2-a]imidazoles 16
R
N
F3C
Cl
N
N
16
In the course of our optimization studies, we prepared and tested
a number of arylalkyl imidazo[1,2-a]imidazoles 15. (Table 2). The
highest binding affinity was displayed by phenethyl ethyl amine
15r (Ki = 6.0 nM), an almost 60-fold advantage over benzyl ethyl
Compd
R
Ki (nM)
Ph
16a
>7000
N
Table 2
Ph
hCRF1R binding affinities of arylalkylaminoimidazo[1,2-a]imidazoles 15
15h
16b
15q
170
190
21
N
Ar
R1
Ph
N
n
N
N
N
F3C
Cl
Ph
N
N
N
N
16c
15r
610
6.0
Ph
Ph
15
Compd
n
Ar
Ph
m-F-C6H4
p-F-C6H4
p-F-C6H4
p-Cl-C6H4
Ph
R1
Ki (nM)
15a
15b
15c
15d
15e
15f
15g
15h
15i
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
CF3CH2CH2
CF3CH2CH2
CF3CH2CH2
CF3CH2
CF3CH2CH2
nBu
Me
nPr
nPr
nPr
nPr
nPr
Et
Et
Et
Me
nPr
Et
Me
Me
Me
Me
CF3CH2
CF3CH2CH2
43
49
34
160
12
130
160
170
28
150
260
350
350
580
4800
180
21
16d
16e
1200
1600
N
N
N
Ph
Ph
p-Cl-C6H4
p-NO2-C6H4
m-F-C6H4
p-F-C6H4
Ph
m,p-Di-Cl-C6H3
o-Me-C6H4
2-Furanyl
Ph
16f
5800
15j
15k
15l
15m
15n
15o
15p
15q
15r
15s
15t
15u
15v
15w
15x
16g
16h
16i
16j
3200
760
N
N
Ph
Ph
2-Pyridyl
3-Pyridyl
4-pyridyl
Ph
6.0
150
4300
1900
7600
350
1900
O
S
1700
920
N
N
Ph

D. Zuev et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3669–3674
3673
Table 4
4. Kasckow, J. W.; Baker, D.; Geracioti, T. D. Peptides 2001, 22, 845.
5. Holsboer, F. J. Psychiatr. Res. 1999, 33, 181.
hCRF1R binding affinities N-cyclopropylamino-N-propylimidazo[1,2-a]imidazoles
6. Banki, C. M.; Karmasci, L.; Bissette, G.; Nemeroff, C. B. Eur.
Neuropsychopharmacol. 1992, 2, 107.
7. Webster, E. L.; Torpy, D. J.; Elenkov, I. J.; Chrousos, G. P. Ann. N.Y. Acad. Sci. 1998,
840, 21.
8. Dzierba, C. D.; Hartz, R. A.; Bronson, J. J. Ann. Rep. Med. Chem. 2008, 43, 3–
23.
X
N
9. Muller, M. B.; Wurst, W. Trends Mol. Med. 2004, 8, 409–415.
10. Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641.
11. Lee, L. F.; Schleppnik, F. M.; Howe, R. K. J. Heterocycl. Chem. 1985, 22, 1621.
12. Byrnes, E. W.; McMaster, P. D.; Smith, E. R.; Blair, M. R.; Boyes, R. N.; Duce, B. R.;
Feldman, H. S.; Kronberg, G. H.; Takman, B. H.; Tenthorey, P. A. J. Med. Chem.
1979, 22, 1171.
N
R1
R5
R4
N
N
R2
13. The assignment of structures of alkylation products 6a and 7a was made on the
basis of the NOE studies. Particularly, a positive NOE effect was observed
between the protons of the C4-methyl and N3-methylene groups in 7a. No
R3
such effect was seen in the studies with analog 6a:
O
Compd
X
R1
R2
R3
R4
R5
Ki (nM)
O
N
Br
O
10a
10b
11b
17a
17b
17c
O
O
2H
2H
2H
2H
Me
CF3
CF3
CF3
CF3
CF3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
MeO
Me
Me
Me
Me
Cl
Cl
Cl
Cl
H
Cl
Cl
61
33
9.1
470
4.2
13
N
H
Br
O
O
N
N
H3C
O
HN
N
nOe
7a
H3C
H
6a
14. The N1-regiospecificity of alkylation of 5b was evidenced by an X-ray
crystallographic analysis of the mono TFA salt of compound 18, derived from
intermediate 6b according to the following scheme:
Imidazo[1,2-a]imidazoles 16a–c, possessing cyclic amino side
chains, displayed significantly lower binding affinities than cor-
responding acyclic amines 15q, 15r and 15h (Table 3). Olefin-
containing 16h was slightly more potent than its saturated
analogs 16d. The potency of methyl piperidines 16e–g were
inferior to that of unsubstituted analog 16d. The introduction
of the electronegative oxygen atom into the piperidine moiety
of 16g led to a decrease in the potency of 16i, while the anal-
ogous substitution with sulfur marginally increased the potency
of 16j.
O
O
º
1) BH3-THF, 80 C
N
2) CH3OH, reflux
F3C
6b
3) AgOTf, sulfolane
1500C
N
N
18
We also briefly investigated a variation in substituents at the
aromatic ring of 2 on binding potency. Both 2-chloro-4,6-dimethyl-
phenyl 17b and 2-methoxy-4-methylphenyl 17c analogs were
nearly as potent as 2,4,6-trimethylphenyl derivative 11b (Table
4). It should be noted, however, that the presence of the 6-chloro
substituent at the imidazo[1,2-a]imidazole core was necessary
for a molecule to sustain high binding affinity. For example,
dechlorinated derivative 17a was approximately 50-fold less active
than 11b. The presence of a polar amide functionality in the side
chain of 10a and 10b led to a decrease in their binding affinities,
compared to that of amine 11c.
In summary, we designed and prepared 6-chloro-2-trifluoro-
methyl-7-aryl-7H-imidazo[1,2-a]imidazol-3-ylmethyl amines as
potent CRF1R receptor antagonists by selective monoamination of
the common chloromethyl intermediate. The presence of the 2-tri-
fluoromethyl group at the core was found to be necessary for
chemical stability. Analogs with amino side chains containing
small alkyl or cycloalkyl groups were found to have the highest
binding affinities.
The X-ray crystal structure of 18 was deposited with Cambridge
Crystallographic Data Centre (deposition number—CCDC 773714).
15. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
16. Malek, J. Org. React. 1988, 36, 249.
17. Analytical data for 12 (double TFA salt): 1H NMR (CD3OD, 500 MHz) d 2.05
(s, 12H), 2.36 (s, 6H), 2.40 (s, 6H), 4.52 (s, 2H), 7.21 (s, 4H), 7.48 (s, 2H), 7.78
(s, 2H). Mass spec.: 558.21 (MH+). In accordance with the related examples24
reported in the literature, the dimerization of 11a to 12 is believed to proceed
by the following mechanism:
Acknowledgments
The authors are grateful to Daniel Smith and Henry Wong (BMS
Chemical Synthesis, Wallingford, CT) for providing them with mul-
ti-gram quantities of ethyl 2-bromo-4-(trifluoromethyl)-1H-imid-
azole-5-carboxylate.
NH
H3C
N
H3C
Cl
N
N
Cl
N
N
HN
N
References and notes
1. Owens, M.; Nemeroff, C. B. Pharmacol. Rev. 1991, 43, 425.
2. Grigoriadis, D. E.; Haddach, M.; Ling, N.; Saunders, J. Curr. Med. Chem. CNS
Agents 2001, 1, 63.
19
11a (TFA salt)
3. Takahashi, L. K. Neurosci. Behav. Rev. 2001, 25, 627.

3674
D. Zuev et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3669–3674
19. Some of the utilized amines were commercially available, while the others
H
were prepared according to the published procedure: see Dubowchik, G. M.;
Michne, J. A.; Zuev, D. Bioorg. Med. Chem. Lett. 2004, 14, 3147.
20. All new compounds gave satisfactory analytical data. For 11c (mono TFA salt):
1H NMR (CD3OD, 500 MHz) d 0.12 (m, 2H), 0.55 (m, 2H), 0.98 (m, 1H), 2.01 (s,
6H), 2.39 (s, 3H), 2.60 (d, J = 6.5 Hz, 2H), 3.36 (m, 2H), 4.21 (s, 2H), 7.12 (s, 2H),
7.61 (s, 1H). Mass spec.: 492.96 (MH+).
N
H3C
N
CH3
N
+ 11a (TFA salt)
N
N
N
N
21. Preparative HPLC Conditions: column XTERRA 30 mm  150 mm S5; injection
volume, 2000 lL; solvent A, CH3OH (10%)/H2O (90%)/TFA (0.1%); solvent B,
Cl
Cl
CH3OH (90%)/H2O (10%)/TFA (0.1%); starting% B, 30; final% B, 100; flow rate
25 mL/min; gradient time, 20 min; end time, 25 min.
20
22. The purity of analogs 11, 15–17 was found to be >90% by reversed phase
analytical LC–MS analysis under following conditions: column—
PHENOMENEX-LUNA 4.6 Â 50 mm S10; solvent A, CH3OH (10%)/H2O (90%)/
TFA (0.1%); solvent B, CH3OH (10%)/H2O (90%)/TFA (0.1%); starting% B, 0; final%
B, 100; flow rate 4 mL/min; gradient time, 2 min; end time, 3 min.
H3C
N
CH3
N
N
N
H2C
N
N
N
23. Membranes were prepared from transformed IMR-32 cells as previously
described,25 and incubated with
[
125I]Tyr-o-CRF (100 pM) and increasing
Cl
Cl
concentrations of test compound for 100 min at 25 °C (assay buffer: 50 mM
Tris (pH 7.2), 10 mM MgCl2, 0.5% BSA, 0.005% Triton X-100, 10 g/mL aprotinin
and 10 g/mL leupeptin. Assays were stopped by addition of ice-cold wash
buffer (50 mM Tris, pH 7.4 and 0.2% BSA). Non-specific binding was defined
with 10 M o-CRF. The present compounds are full antagonists of the CRF1R as
l
12
l
18. This stabilizing effect of the trifluoromethyl group has been previously
observed in related systems: see (a) Dubowchik, G. M.; Michne, J. A.; Zuev,
D.; Schwartz, W.; Scola, P. M.; James, C.; Ruediger, E.; Pin, S.; Burris, K. D.;
Balanda, L.; Gao, Q.; Fung, L.; Fiedler, T.; Browman, K. E.; Taber, M. T.;
Zhang, J. Bioorg. Med. Chem. Lett. 2003, 13, 3997; (b) Han, X.; Michne, J. A.;
Pin, S. S.; Burris, K. D.; Balanda, L. A.; Fung, L. K.; Fiedler, T.; Browman, K. E.;
Taber, M. T.; Zhang, J.; Dubowchik, G. M. Bioorg. Med. Chem. Lett. 2005, 15,
3870.
l
determined by their ability to inhibit CRF stimulated cAMP production in IMR-
32 cells.
24. (a) Kamel, M. M.; Nabih, I.; Nasr, M. E.; Abbasi, M. M. Pharmazie 1985, 40, 622;
(b) Abbasi, M.; Nasr, M.; Zoorob, H. H.; Michael, J. M. J. Heterocycl. Chem. 1978,
15, 649; (c) Frydman, R. B.; Reil, S.; Frydman, B. Biochemistry 1971, 10, 1154; (d)
Burke, W. J.; Nasutavicus, W. A.; Weatherbee, C. J. Org. Chem. 1964, 29, 407.
25. Dieterich, K. D.; DeSouza, E. B. Brain Res. 1996, 733, 113.