Arylamidrazones as novel corticotropin releasing factor receptor antagonists

Article abstract of DOI:10.1021/jm025512y

The arylamidrazones have been found to be potent corticotropin releasing factor (CRF) receptor antagonists structurally distinct from previously reported CRF₁ antagonists. Attempts to modify the arylamidrazone core suggested an important role f

Full text of DOI:10.1021/jm025512y

© Copyright 2002 by the American Chemical Society
Volume 45, Number 11
May 23, 2002
Letters
Ar yla m id r a zon es a s Novel Cor ticotr op in
Relea sin g F a ctor Recep tor An ta gon ists
Dean M. Wilson, Andreas P. Termin, Long Mao,
Michele M. Ramirez-Weinhouse,
Valentina Molteni, and Peter D. J . Grootenhuis*
Bristol Myers Squibb Pharma Research Labs,
4570 Executive Drive, Suite 400,
San Diego, California 92121
Keith Miller, Susan Keim, and Gwendolyn Wise
Bristol Myers Squibb Pharmaceutical Research Institute,
P.O. Box 80500, Wilmington, Delaware 19880
Received February 16, 2002
F igu r e 1. Some advanced small-molecule CRF receptor
antagonists.13,16,17
Abstr a ct: The arylamidrazones have been found to be potent
corticotropin releasing factor (CRF) receptor antagonists struc-
turally distinct from previously reported CRF1 antagonists.
Attempts to modify the arylamidrazone core suggested an
important role for the anilino NH moiety. The right-hand-side
2-nitro feature in lead 1 could be replaced with substituents
methyl, chloro, cyano, or trifluoromethyl with a 4- to 10-fold
reduction in receptor binding. With appropriate left-hand-side
modifications, this potency loss could be recovered.
outcome and subtype specificity has yet to be established
and remains an active area of research.
Direct intracerebroventricular (icv) injection of CRF
itself elicits a behavioral and physiological cascade very
similar to that resulting from environmental sources of
stress.5 In addition to these normal functions, CRF has
been invoked in a wide variety of pathological conditions
ranging from anxiety and depression,6 substance abuse,7
eating disorders,8 premature parturition,9,10 immune
disease,11 and gastrointestinal maladies.12
Potent small-molecule CRF receptor antagonists have
been discovered, several of which are under early
clinical evaluation. Only recently have data become
available detailing in vivo profiles of development
compounds, since most preclinical and clinical investi-
gations remain active areas within the pharmaceutical
industry. Three recent examples are illustrated in
Figure 1.
In tr od u ction . The role of corticotropin releasing
factor (CRF) in the physiology of stress has been an area
of active research since the isolation of the 41 amino
acid protein in 1981.1 It has since been established that
CRF (also known as corticotropin releasing hormone,
CRH) modulates the activity of the hypothalamus-
pituitary-adrenal axis (HPA), regulating “fight or
flight” responses to stressors. Two subtypes of CRF
receptors have been identified, CRF1 and CRF2, with
the latter existing as splice variants R, â, and γ.2 While
most drug discovery efforts have focused on CRF1
receptors, CRF2 receptor subtypes have begun to attract
attention,3 especially since the discovery of subtype-
specific ligands.4 The overall correlation between clinical
Pfizer has described CP-154,526,13 and the effects of
chronic adminstration in rat were shown to be anxi-
olytic.14 Adrenal insufficiency, a plausible adverse effect,
was not observed, consistent with the clinical utility for
small-molecule CRF receptor antagonists. The Neuro-
crine compound NBI 30775 (R121919) has advanced to
* To whom correspondence should be addressed. Phone: 858-625-
6401. Fax: 858-625-9293. E-mail: pgrootenhuis@combichem.com.
10.1021/jm025512y CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/26/2002

2124 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Letters
Ta ble 1. Ki (nM) Data for Derivatives of 125
compd
X
R2
Ki (nM)
F igu r e 2. Representative small-molecule CRF receptor an-
1
8
9
NH
NMe
O
NH
NMe
O
NH
NMe
O
NH
NMe
S
NH
NMe
NH
NMe
O
2-NO2
2-NO2
2-NO2
H
51
8600
tagonist chemotypes.18
>10000
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2720
H
H
>10000
>10000
538
>10000
>10000
417
>10000
>10000
415
2-CF3
2-CF3
2-CF3
2-Cl
2-Cl
2-Cl
2-CN
2-CN
2-Me
2-Me
2-Me
2-Me
2-SO2Me
2-SO2NH2
4-Me
4-Br
F igu r e 3. Initial lead arylamidrazone 1.
>10000
216
>10000
>10000
>10000
>10000
>10000
2285
F igu r e 4. Arylamidrazone strategy: optimization of LHS,
RHS, and core.
S
NH
NH
NH
NH
Sch em e 1a
1459
reported. After the compound was tested against the
human CRF1 receptor, its Ki value was determined to
be 51 nM.22
Efforts were directed toward several potential issues.
First, the role of individual structural features in
receptor binding was unknown, information best ac-
quired by exploring the structure-activity relationships
(SAR) for the series. Second, several chemical features,
including the nitro group, the aniline moieties, and the
arylamidrazone core, were seen as potential liabilities
in a drug candidate. These areas were therefore targeted
for investigation.
a
o
Conditions: (a) concentrated HCl, NaNO2, H2O, 0 C, 30 min;
(b) 2,4-pentanedione, NaOAc, 3:1 H2O/EtOH, 0 °C to room tem-
perature, 3 h; (c) 2.5:1 AcOH/Ac2O, NaOAc, Br2, 0 °C to room
temperature, 30 min; (d) ArNH2, ArNHMe, ArSH, or ArOH, DMF,
I-Pr2NEt, room temperature, o/n.
an open label phase IIa trial,15 which, although pre-
liminary, suggested reductions in clinical scoring of
anxiety and depression. Rodent in vivo data for the
compound were also recently disclosed.16 Sanofi-Syn-
thelabo has also described the rodent in vivo profile of
SSR125543A.17
Although multiple general chemical classes of CRF
receptor antagonists have been identified (Figure 2),18
there is still considerable interest in novel, unprec-
edented chemotypes, especially given the substantial
prior art.19 Furthermore, potential chemotype-specific
pharmacokinetic, selectivity, or clinical liabilities pro-
vide ample incentive for unique antagonists. It is within
this context that we sought to develop structurally
unprecedented antagonists of CRF.
Ch em istr y
To systematically explore the SAR of the arylamidra-
zone series, the structure was divided into three parts
(Figure 4) to elucidate the effect on receptor binding
(vide infra).
Analogues were prepared in a three-step sequence
starting with commercially available anilines 2. In situ
diazotization followed by condensation with 2,4-pen-
tanedione gave the diketohydrazones 3, which were
converted to the hydrazonyl bromides 4 by bromination
in acetic acid/acetic anhydride.23 Reaction of the hydra-
zonyl bromides with the appropriate aniline, phenol, or
thiophenol gave the aza, oxo, and thia derivatives 5
(Scheme 1).24
To generate novel leads, our proprietary screening
library known as the universal informer library (UIL)
was evaluated. This chemically diverse screening library
(13 600 compounds) was designed to generate an opti-
mal amount of information from the screening data
(both actives and inactives), as described previously.20
When the UIL was screened against the rat CRF1
receptor,21 lead compound 1 was identified (Figure 3).
Compound 1 was an arylamidrazone, a novel struc-
tural class for which no CRF antagonism had been
Op tim iza tion a n d SAR. Holding the 3-chlorophenyl
moiety constant (LHS), arylamidrazone derivatives were
synthesized modifying both the phenylhydrazone sub-
stitution (RHS) and the core connectivity “X”. As shown
in Table 1, the 2-nitrophenyl substituent in 1 (RHS)
could be replaced with small substituents such as
methyl, chloro, cyano, or trifluoromethyl without com-
plete elimination of receptor binding. Although potency
was reduced 4- to 10-fold, (13, 16, 19, 21), the possibility
of compensatory optimizations elsewhere in the mol-

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2125
Ta ble 2. Ki (nM) Data for LHS and RHS Derivatives of 125,a
Next, the RHS 2-nitro replacements identified were
held constant and the LHS aromatic substituents were
varied. Fortunately, it was discovered that through
appropriate LHS modifications, the 4- to 10-fold potency
loss observed upon nitro replacement could be recovered.
For example, 3-fluoro derivatives (34, 46) and 3-ethynyl-
substituted 51 led to compounds more potent than the
original lead 1, sans nitro, thus achieving an important
optimization objective. Similar 3-ethynyl derivatives 39
and 63 were essentially equipotent. These results are
summarized in Table 2.
compd
R1
R2
Ki (nM)
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
H
2-Cl
3-Cl
4-Cl
3-Me
3-F
3-OMe
3-OEt
3-SMe
3-CN
3-ethynyl
3-CF3
H
2-Cl
3-Cl
4-Cl
3-Me
3-F
3-OMe
3-OEt
3-SMe
3-CN
3-eth yn yl
3-CF3
H
2-Cl
3-Cl
4-Cl
3-Me
3-F
3-OMe
3-OEt
3-SMe
3-CN
3-ethynyl
3-CF3
H
2-Cl
3-Cl
4-Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
526
>10000
216
1832
526
43
1403
>10000
>10000
>10000
62
Con clu sion . We have discovered a novel series of
CRF1 receptor antagonists that are structurally novel
and distinct from other known CRF antagonists. Pre-
liminary attempts to modify the arylamidrazone core
suggested an important role for the anilino NH moiety,
in contrast to the customary obligate hydrogen bond
acceptor.3 Retention of this feature and optimization of
substituents on the LHS and RHS aromatic rings
identified several des-nitro compounds more potent than
1. The polarity (calculated log P ) 3-5) of the com-
pounds contrasts with those of most known CRF an-
tagonists, which are typically more lipophilic,18 sug-
gesting potential physicochemical and pharmacokinetc
benefits. Further in vitro and in vivo studies on the
arylamidrazone series shall be disclosed in due course.
291
299
>10000
417
3867
115
43
652
>10000
>10000
nd
Cl
Cl
Cl
35
nd
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
2261
>10000
538
>10000
1422
197
Ack n ow led gm en t. The authors thank Mark Suto,
Peter Myers, Rich Wilde, and Paul Gilligan for their
support and helpful discussions.
6953
>10000
>10000
>10000
66
>10000
6230
>10000
2720
>10000
4708
>10000
1079
>10000
415
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, 1H NMR, LC/MS, and HRMS data for compounds
shown in tables. This material is available free of charge via
the Internet at http://pubs.acs.org.
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H
H
H
H
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2207
650
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a
Compounds with Ki < 51 nM are labeled in bold.
ecule suggested plausible non-nitro-containing ana-
logues. Potential formal charge bioisosteres for the nitro
substituent gave inactive compounds (25, 26). Substitu-
tion at the 2 position was also favored over 4-substituted
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J M025512Y