Synthesis and structure-activity relationships of heteroaryl substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCR1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.01.024

Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.

Full text of DOI:10.1016/j.bmcl.2008.01.024

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1318–1322
Synthesis and structure–activity relationships of heteroaryl
substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione
CXCR2/CXCR1 receptor antagonists
a,
a
a
a
Younong Yu,a,* Michael P. Dwyer, Jianping Chao, Cynthia Aki, Jianhua Chao,
Biju Purakkattle,a Diane Rindgen,b Richard Bond,c Rosemary Mayer-Ezel,c
James Jakway,c, Hongchen Qiu,c R. William Hipkin,c James Fossetta,c
Waldemar Gonsiorek,c Hong Bian,c Xuedong Fan,c Carol Terminelli,c Jay Fine,c
Daniel Lundell,c J. Robert Merritt,d Zhenmin He,d Gaifa Lai,d
Minglang Wud and Arthur Taverasa,à
*
aDepartment of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bDepartment of Drug Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
cDepartment of Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
dPharmacopeia Drug Discovery Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA
Received 15 November 2007; revised 7 January 2008; accepted 8 January 2008
Available online 11 January 2008
Abstract—Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1
receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as
oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown
to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts,
was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral expo-
sure in rat versus other heterocyclic derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Interleukin-8 or IL-8 (CXCL8) is a proinflammatory
member of the CXC chemokine family which plays a
critical role in the migration of neutrophils to sites of
inflammation and tissue injury.1 CXCL8 is known to
bind to two G-protein coupled, seven transmembrane
receptors which were cloned and identified as CXCR1
and CXCR2.2,3 CXCR2 binds with high affinity to
CXCL8 as well as other ELR+ chemokines such as
GCP-2 (CXCL6), ENA-78 (CXCL5), and Gro-a
(CXCL1), while CXCR1 is less promiscuous and binds
to both CXCL8 and CXCL6 with high affinity.4 When
CXCL8 interacts with the CXCR2 and CXCR1 recep-
tors on neutrophils, an intracellular response occurs to
include calcium flux, degranulation, and subsequent
chemotaxis.5 In humans, elevated levels of CXCL8
and CXCL1 have been observed in individuals with
arthritis, asthma, and COPD, suggestive of the critical
role that these chemokines play in such processes.6 In
addition, the importance of small molecule antagonists
of CXCL8 receptors has been supported by the normal
physiology of mouse gene CXCR2 knockouts.7
Keywords: CXCR2 receptor; CXCR1 receptor; 3,4-Diaminocyclobut-
3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists; Inter-
leukin-8.
In 1998, Widdowson and coworkers reported the first
small molecule CXCR2 antagonists in the diaryl urea
class represented by compound 1.8 Several additional
series have been reported since9 and the area has been
recently reviewed.10 The centerpiece of our efforts has
been the utilization of the 3,4-diaminocyclobut-3-ene-
*
Corresponding authors. Tel.: +1 908 740 5156; fax: +1 908 740 7152
(Y.Y.); e-mail: younong.yu@spcorp.com
Present address: Abbott Bioresearch Center, 100 Research Drive,
Worcester, MA 01605, USA.
à
Present address: Biogen Idec, 14 Cambridge Center, Cambridge, MA
02142, USA.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.024

Y. Yu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1318–1322
1319
1,2-dione motif for the preparation of potent CXCR2/
H
CXCR1 receptor antagonists.11 Recently, we repor-
ted11b the emergence of several heterocyclic derivatives
(thienyl and furyl) in this structural series which culmi-
nated in the identification of 2 (SCH 527123), a potent
CXCR2/CXCR1 receptor antagonist (Fig. 1) which is
currently under clinical investigation.11c During the
course of those investigations, substitution at the C5-po-
sition of the furyl motif was shown to be required to at-
tain good oral exposure in rat albeit at the expense of
binding affinity for the CXCR1 receptor.11b Based upon
these observations, we became interested in further
exploring the role of substitution/electronics in the furyl
class represented by 2 as well as the possibility of iden-
tifying additional heterocyclic motifs that might serve
as potent CXCR2/CXCR1 receptor antagonists. Herein,
the details of these comprehensive SAR efforts are
summarized.12
a or
H2N
O
R
O
O
R
b, c, d
4
3
O
O
N
O
N
OEt
H
5
OH
N
N
H
N
R
H
EtOH
O
OH
6-40
Scheme 1. Reagents and conditions: (a) LiN(TMS)2 then EtMgBr or
(b) EtMgBr, Et2O; (c) DPPA, DBU; (d) PPh3, H2O.
c
O
a, b
O
BocHN
H2N
.HCl
Having previously established the critical elements of
the a-side chain in this series of derivatives (as exempli-
fied by 2) with regard to both stereochemistry [(R)-pre-
ferred over (S)] and length (ethyl) for optimal receptor
binding affinities and good oral exposure in rat,11b we
focused our initial efforts upon the rapid preparation
of substituted furyl and heteroaryl derivatives bearing
the optimal racemic a-ethyl side chain. The initial
SAR generated in the racemic series served to focus fol-
lowup synthetic efforts of the most interesting analogs
with an asymmetric synthesis according to known
methodology.11b,13
Br
42
R
41
O
O
O
N
N
N
H
H
O
OH
R
22-25
Scheme 2. Reagents and conditions: (a) RB(OH)2, Pd(PPh3)4, K3PO4,
DME/H2O; (b) 4 N HCl/dioxane; (c) 5, EtOH, Et3N, rt.
Table 1. Receptor binding affinities for racemic furyl derivatives
The synthesis of the racemic heteroaryl derivatives14 is
depicted in Schemes 1 and 2. Beginning with the com-
mercially available or prepared heterocyclic aldehydes
3, treatment with LiN(TMS)2 followed by addition of
EtMgBr afforded the desired racemic amine adducts 4
according to the procedure of Hart in a single step.15
Alternatively, aldehydes 3 were converted to the amine
via a three-step protocol which relied upon an alcohol
to azide transformation17 followed by treatment with
PPh3/H2O (Scheme 1). Coupling with the previously de-
scribed dimethyl amide cyclobutenedione adduct 5,11b
which was prepared in three steps from nitrosalicyclic
acid, afforded the final adducts 6–40. The aryl and het-
eroaryl 4-substituted furyl derivatives (22–25) were pre-
pared by Suzuki coupling of various boronic acids with
the Boc-protected 4-Br adduct 42 followed by deprotec-
tion and coupling with intermediate 5 (Scheme 2).16
O
O
O
N
N
N
H
H
R
O
OH
Compound
R
IC50 of
IC50 of
CXCR2a (nM) CXCR1a (nM)
6
7
5-H
5.0
5.7
4.1
4.7
4.8
17.2
6.8
2.8
94
67
99
5-Me
5-Et
5-Br
5-Cl
8
854
463
275
6062
568
182
nab
naa
4870
naa
3376
3434
100
93
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
5-CF3
5-CF2H
5-CH2OH
5-CH2N(Me)2
5-CON(Me)2
5-(2-Cl)Ph
5-(2-CF3)Ph
5-(3-Cl)Ph
5-(3-CF3)Ph
4-Cl
171
49
150
58
Table 1 summarizes the SAR studies for the substituted
furyl derivatives. At the C5 position, the CXCR2 bind-
ing affinity was well maintained with increasing size of
substitution (H vs Me vs Et, etc.) however the CXCR1
receptor was less tolerant with the binding affinity drop-
87
4.5
5.0
6.1
9.5
8.2
4-Br
4-Ph
150
526
221
345
4-(4-Pyridyl)
4-(3-Thienyl)
O
O
4-(3,5-Dimethyl-4- 7.6
isoxazolyl)
O
H2N
O
N
S
O
N
H
N
H
Cl
N
N
26
27
2,3-Benzofuran
3-Br
3.5
16.5
412
1023
H
H
O
OH
Cl
O
OH
2 (SCH 527123)
1 (SB-332235)
a Values are means of two (n = 2) runs. See Ref. 11b for assay details.
b na, not active at >10,000 nM.
Figure 1. CXCR2 and CXCR2/CXCR1 receptor antagonists.

1320
Y. Yu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1318–1322
Table 2. Receptor binding affinities for racemic heterocyclic
derivatives
ping off with increasing size of substitution (6–10). The
5-H analog (6) displayed the best affinity for the CXCR1
receptor indicative of the tight SAR at this position.
Interestingly, trifluoromethyl analog 11 demonstrated
a substantial loss in binding affinity for both chemokine
receptors compared both to the CF2H analog 12 and Me
derivative 7 suggestive of potential electronic consider-
ations at this site. While methanol derivative 13 was well
tolerated at the C5 position, incorporation of basic fun-
tionality, dimethylamido, or substituted phenyl motifs
resulted in a dramatic loss in binding affinity for both
receptors (15–19). The C4 position of the furyl motif
was found to be much more tolerant of functionality
as demonstrated by the comparable CXCR2 affinities
with improved CXCR1 binding affinity of the 4-halo
derivatives (20 and 21) and phenyl derivative (22) versus
the corresponding C5 adducts (9, 10, and 16–19). In
addition, a variety of heteroaryl motifs were found to
be tolerated at this position albeit with slightly poorer
affinity for both receptors versus the 4-halo derivatives.
Owing to concern over potential C5 oxidation in this
series, 4,5-disubstituted analogs such as 26 were pre-
pared and found to be reasonably well tolerated for both
chemokine receptors. However, substitution at the C3
position of the furan ring was not well tolerated by
either receptor as demonstrated by the 3-Br analog (27).
O
O
N
N
N
R
H
H
O
OH
Compound
R
IC50 for
CXCR2a (nM)
IC50 for
CXCR1a (nM)
O
28
29
30
31
32
33
34
8.6
795
805
703
302
224
289
812
N
N
N
10.9
9.8
9.8
7.5
8.2
8.0
O
N
S
O
N
N
O
O
N
Having completed the rapid survey of racemic substi-
tuted furyl derivatives, attention was turned toward
the preparation of other heterocyclic derivatives to ex-
plore the feasibility of replacing the furan ring. These
analogs were prepared according to the general syn-
thetic route laid out in Scheme 1 and the receptor bind-
ing data are summarized in Table 2. In general, the
heterocyclic compounds showed reduced binding
affinity toward the CXCR2 receptor versus the furyl
derivatives in Table 1 with variable affinity for the
CXCR1 receptor based upon structure. While the 2-
and 3-thienyl analogs (35 and 36) displayed comparable
binding affinities for both chemokine receptors, the
analogous furyl derivatives (6 and 34) displayed diver-
gent profiles illustrating the sensitivity of the chemokine
receptors to the placement of the heteroatom within the
ring. Interestingly, the 2-thienyl series (36–38) demon-
strated analogous SAR trends to the corresponding fur-
yl derivatives while basic heterocycles such as 39 or 40
were not well tolerated by either the CXCR2 or CXCR1
receptor. A couple of five-membered heterocyclic ana-
logs (32 and 35) emerged from these efforts which dis-
played reasonable potency to merit further
investigation.
O
S
35
36
5.8
6.2
165
179
S
S
37
38
39
40
6.2
21
1110
1372
nab
Cl
S
Cl
N
815
50
2856
N
a Values are means of two (n = 2) runs. See Ref. 11b for assay details.
b na, not active at >10,000 nM.
derivatives such as 47 and 48 showed good receptor
binding affinities, modest oral exposure in rat precluded
further progression of these compounds. Interestingly,
the 2-pyridyl analog 49 showed improved binding affin-
ities for both receptors versus the 4-pyridyl analog 40
suggestive of a key role that the placement of the hetero-
atom in the ring plays on the profile.
Based upon the broad SAR screen of racemic deriva-
tives from Tables 1 and 2, a focused series of optically
pure (R)-ethyl substituted heteroaryl analogs17 were pre-
pared according to our previously disclosed route11b
(Scheme 3). The binding affinities for the CXCR2 and
CXCR1 receptors as well as oral exposure data in
rat18 are summarized in Table 3. The 4-substituted fur-
ans 45 and 46 demonstrated an excellent combination
of superior CXCR2 and CXCR1 receptor binding affin-
ities as well as oral exposure in rat consistent with previ-
ous observations for this series. While heterocyclic
In an effort to further characterize and prioritize the
derivatives found in Table 3, several analogs were exam-
ined for their ability to inhibit CXCR2- and
CXCR1-mediated chemotaxis using recombinant cells

Y. Yu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1318–1322
Table 4. Ba/F3 chemotaxis data19 for 46, 47, and 49
1321
O
a, b
O
O
TMSO
N
H
R
N
N
N
R
3
H
43
R
H
H
O
OH
O
O
Compound
IC50 for
hCXCR2a (nM)
IC50 for
hCXCR1a (nM)
c, d, e
N
N
N
R
H
H
46
47
49
2.0
12.2
4.5
917
nab
nab
O
OH
44-49
a Values are means of at least two (n = 2) runs.
b na, not active at >10,000 nM.
Scheme 3. Reagents and conditions: (a) R-valinol, MgSO4, CH2Cl2;
(b) TMSCl, Et3N; (c) EtLi, Et2O; (d) H5IO6, MeNH2 (40% in H2O); (e)
5, EtOH, rt.
(Ba/F3-hCXCR2 and Ba/F3-hCXCR1).19 From Table
4, furyl derivative 46 displayed superior potency to inhi-
bit both CXCR2- and CXCR1-mediated chemotaxis
versus the other heterocyclic analogs 47 and 49. As
one might expect based on their binding activity (Table
3), these derivatives more potently inhibited CXCR2-
mediated chemotaxis relative to their activity at CXCR1
(Table 4). However, the relative binding potencies of
compounds 46, 47, and 49 at CXCR1 did not effectively
capture differences in the compounds functional potency
in blocking chemotaxis through this receptor.20 The
implementation of this cell-based assay was critical in
differentiating derivatives based upon functional activity
versus that otherwise look comparable based upon the
receptor binding affinities reported in Table 3. The func-
tional data presented in Table 4 are in excellent agree-
ment with the pharmacological characterization of
compound 2 as an allosteric antagonist of both the
CXCR2 and CXCR1 receptors but whose functional ef-
fects are mediated primarily through the CXCR2
receptor.20
In conclusion, this work has illustrated the critical role
of the heterocycle and requisite substitution around het-
erocycle plays on the overall biological profile of the 3,4-
diaminocyclobut-3-ene-1,2-dione
CXCR2/CXCR1
receptor antagonists. These SAR studies have illustrated
the tolerant nature of the CXCR2 receptor versus the
more sensitive CXCR1 receptor to both structural and
electronic considerations. While several heterocyclic
replacements of the furyl motif found in 2 demonstrated
reasonable receptor binding affinities, modest oral expo-
sure in rat and lack of suitable functional activity pre-
cluded further advancement of these derivatives. The
furyl series, particularly the 4-halo analogs, was found
to possess superior chemokine receptor binding affini-
ties, functional activity, and oral exposure in rat com-
pared to the broad panel of other heterocyclic
derivatives. Additional studies21 profiling the further
utility of the furyl class of 3,4-diaminocyclobut-3-ene-
1,2-dione CXCR2/CXCR1 receptor antagonists will be
reported in due course.
Table 3. Receptor binding affinities and rat exposure data for optically
pure derivatives
O
O
N
N
N
R
H
H
O
OH
Compound
R
IC50 for
IC50 for
Rat AUCb
CXCR2a CXCR1a (10 mpk, po)
(nM)
4.6
(nM)
244
(lM h)
O
Cl
44
—
O
O
45
46
47
48
49
3.8
3.5
6.3
3.4
3.3
62
55
21.5
33.4
3.7
—
Cl
Br
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