Aryltriflates as a neglected moiety in medicinal chemistry: A case study from a lead optimization of CXCL8 inhibitors

Article abstract of DOI:10.1021/ml2001533

Interleukin-8 and growth related oncogene-α-chemokines (formerly CXCL8 and CXCL1, respectively) mediate chemotaxis of neutrophils to inflammatory sites via interactions with two transmembrane receptors, the type A CXCL8 receptor (CXCR1) and the type B CXC

Full text of DOI:10.1021/ml2001533

LETTER
pubs.acs.org/acsmedchemlett
Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case
Study from a Lead Optimization of CXCL8 Inhibitors
Alessio Moriconi,*,† Chiara Bigogno,‡ Gianluca Bianchini,† Antonio Caligiuri,‡ Anna Resconi,‡
Massimo G. Dondio,‡ Gaetano D’Anniballe,† and Marcello Allegretti†
†Research Center, Dompꢀe s.p.a., via Campo di Pile, 67100 L’Aquila, Italy
‡DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy
S Supporting Information
b
ABSTRACT: Interleukin-8 and growth related oncogeneꢀR-
chemokines (formerly CXCL8 and CXCL1, respectively) med-
iate chemotaxis of neutrophils to inflammatory sites via inter-
actions with two transmembrane receptors, the type A CXCL8
receptor (CXCR1) and the type B CXCL8 receptor (CXCR2).
In a previous work, we published the molecular modeling-
driven structure activity relationship (SAR) results culminated
in the discovery of R-(ꢀ)-2-[(40-trifluoromethanesulphonyloxy)
phenyl]-N-methanesulfonyl propionamide (19), in which an
unusual aryltriflate moiety was embedded. Although triflates
are broadly used in organic synthesis, this group is scarcely used
in medicinal chemistry programs. Here we detail the drug profiling-driven approach used for the selection and characterization of 19,
the most potent dual CXCR1 and CXCR2 noncompetitive inhibitor described to date. Reported data suggest that the aryltriflate
moiety might represent a valid choice for the selection of clinical candidates with suitable druglike properties.
KEYWORDS: Aryltriflate, CXCR1, CXCR2, chemokine, dual noncompetitive inhibitor, drug profiling
XCL8 and CXCL1 belong to the class of chemokines or
“chemotactic cytokines”, a group of low molecular weight
programs due to the wide availability of structurally diverse
phenols.14ꢀ16 Nevertheless, very few examples of lead compounds
orclinical candidatesembeddinganaryltriflate moiety are reported
in the literature and, at the time of this study, focused research
performed on the Thomson Reuter Integrity portal by using the
triflate as entry query highlighted that six out of the thirteen
molecules reported in the preclinical or clinical phase derived from
Dompꢀe proprietary programs.17
Here, we describe the approach followed for the discovery and
characterization of novel CXCR1/CXCR2 inhibitors, typified by
R-(ꢀ)-2-[(40-trifluoromethanesulphonyloxy)phenyl]-N-methane-
sulfonyl propionamide (19), selected as clinical candidate.
The aim of this communication is to point out the excellent in
vitro and in vivo behavior of the aryltriflate group, thus encoura-
ging future efforts aiming to incorporate this moiety in future
clinical candidates with appropriate druglike properties.
Based on molecular modeling and mutagenesis studies, the
triflate group was selected as an ideal moiety due to its ability to
establish hydrophobic interactions with CXCL8 receptors with
minimal steric hindrance.13 In agreement with previously
published SAR and coherently with the proposed binding
mode, different functionalizations of the phenylpropionyl scaf-
fold, including aromatic/aliphatic amides, hydroxamates, and
C
8ꢀ14 kDa proteins that regulate the trafficking of leukocytes in
the inflamed tissues and other biological processes, including cell
growth, angiogenesis, and hematopoiesis.1ꢀ3 CXCL8 binds
CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for
CXCR2. Both receptors belong to the seven transmembrane
G-protein-coupled receptors (GPCRs) superfamily, sharing 78%
amino acid identity.4
The CXCL8 receptor activation has been implicated as a key
event in severe chronic diseases, including rheumatoid arthritis,
chronic obstructive pulmonary disease, Alzheimer’s disease,
melanoma, and psoriasis.5ꢀ9 To date, a limited number of small
molecular weight CXCL8 inhibitors have been disclosed in the
literature.10,11 Reparixin (1), a potent inhibitor of CXCR1,
stemmed from our internal medicinal chemistry programs, was
selected as candidate drug after demonstration of its efficacy in
several ischemia/reperfusion experimental models.12 However,
its short half-life in humans and the weak activity to CXCR2
limited the exploitation of its potential use for the treatment of
chronic conditions. In an earlier paper, SAR results of potent
CXCR1/CXCR2 noncompetitive inhibitors were disclosed.13 As
the main outcome of the work, aryltriflates showed a long plasma
half-life in the tested species and dual activity to CXCR1 and
CXCR2. Aryltriflates are excellent substrates for Stille and Suzuki
cross-coupling reactions, Heck reactions, and BuchwaldꢀHartwig
reactions and are used as intermediates in medicinal chemistry
Received: June 23, 2011
Accepted: August 7, 2011
Published: August 07, 2011
r
2011 American Chemical Society
768
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LETTER
Table 1. Biological Activity of Compounds 1ꢀ22
a % inhibition ( SD (n = 3) on the CXCL8-induced human polymorphonucleate (PMN) chemotaxis at 10ꢀ8 M. b % inhibition ( SD (n = 3) on the
CXCL1-induced human PMN chemotaxis at 10ꢀ8 M. c NA not active.
acylsulfonamides matched well with the desired biological
activity.13
R-(ꢀ)-2-(4-Trifluoromethanesulfonyloxy)phenylpropionic
acid (2) (Table 1) was the first compound selected with an
optimal biological activity profile. However, its structural
similarity to the family of nonsteroidal antiinflammatory drugs
(NSAIDs) prompted us to investigate also alternative candi-
dates, since several in vitro and in vivo studies highlighted the
susceptibility of phenylpropionic acids to undergo metabolic
chiral inversion by the formation of a coenzyme A thioester
intermediate.18,19
The paucity of medicinal chemistry data prompted us to be
careful to consider the potential usefulness of this group; thus, the
identified molecules were profiled along a screening cascade to
ensure suitable developability potential. We assume that presump-
tion of the biological liability of this moiety discouraged medicinal
chemists from further investigation due to the possible in vivo
formation of potentially toxic phenol derivatives and trifluoro-
methanesulfonic acid; thus, metabolic stability was carefully ex-
amined. The synthesis of compounds 1ꢀ22 (Table 1) is reported
in the Supporting Information while the biological activity was
assessed as previously described.13
Heteroaromatic amides (Table 1, 3ꢀ11) were the first class
investigated.
In fact, on the basis of reported SAR studies, the activity of
heteroaryl derivatives is consistent with the formation of an
intramolecular hydrogen bond involving the heteroatom in the
2-position as acceptor that plays a key role in shifting the amido/
imido equilibrium.13 The 2-aminopyridine derivative 3 was the
The methodology used to prioritize the choice of preclinical
candidates was the assembly of a specific screening grid defined
for each chemical class.
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LETTER
Table 2. CYP Inhibition, Solubility, and log D of Aromatic
Amides 3ꢀ11
Table 4. Rat Microsomal Stability, Solubility, and log D of 2
and 17ꢀ20
rat microsomesa (%)
sol (mg/mL) @ 7.4b
log D @ 7.4b
CYPa (%)
cmpd
2
100
80
>10
0.6
0.2
6.4
1.9
ꢀ0.8
1.4
cmpd 1A2 2D6 3A4 2C9 2C19 sol (mg/mL) @ 7.4b log D @ 7.4b
17
18
19
20
3
<5 21 15 37
36 26 52 53
<5 40 66 50
15 <5 44 70
97
87
70
90
21
0.14
2.9
3.4
2.2
2.3
1.4
1.6
4.0
2.9
3.9
75
2.3
4
0.003
0.013
0.03
100
NDc
ꢀ0.6
ꢀ0.2
5
a % remaining compound after 30 min in liver rat microsomes.
6
b ACDPhysChem Ver. 12. c ND: not determined.
7
<5 <5
8
<5
0.06
8
NDc ND ND ND ND
0.05
9
14 56 52 73
<5 38 82 87
16 <5 60 60
94
94
90
0.0006
0.004
0.002
the affinity for the heme iron, failed to minimize the CYP
inhibition.
As second step, a series of hydroxamic acid derivatives was
investigated (Table 3).
10
11
a % inhibition at 10 μM in the indicated CYP isoform. b ACDPhysChem
Ver. 12. c ND: not determined.
Compounds 12ꢀ14 showed activity on both CXCR1 and
CXCR2. However, hydroxamic acids may be hydrolyzed to the
corresponding carboxylic acid under physiological conditions,
and a recent work rationalizes the structureꢀplasma stability
relationships for hydroxamates.20 Compounds 12ꢀ14 con-
firmed a remarkable chemical stability (>98% at pH = 7.4;
Supporting Information), a good metabolic stability in rat liver
microsomes (about 75%), and an excellent rat plasma stability
(average 90%) (Table 3). O-Alkylation of the hydroxamate
group (15 and 16) led to an increase of log D but, unfortunately,
to a partial loss of biological activity too (Table 3). Further
enlargement of the hydrophobic substituent by either O- or N-
alkylation was not tolerated, leading to the loss of biological
activity (data not shown). The experimental plasma half-life of
hydroxamates 12ꢀ14 after intravenous administration in ro-
dents was less than 1 h. It is noteworthy that neither in vitro nor
in vivo metabolites bearing a phenolic moiety were detected and
that the short half-life was associated with the metabolic liability
of the hydroxamate function and with the rapid clearance
through phase II metabolic reactions (data not shown).
On the basis of the above results, R-(ꢀ)-2-(4-trifluorometha-
nesulfonyloxy)phenylpropionic acid (2), the primary amide 17,
the alkyl amide 18, and acylsulfonamides 19 and 20 were also
evaluated.
Primary amide 17 and related N-isopropyl derivative 18 were
equipotent to both CXCR1 and CXCR2, showing also relatively
low log D values (Table 4). Acidic compounds 2, 19, and 20 were
found to be dual CXCR1 and CXCR2 inhibitors also with an
excellent solubility (>1 mg/mL). Coherently with the observed
stability of the 4-triflate-phenylpropionic moiety, a good meta-
bolic stability was observed in rat microsomes for 17 and 18, but
the exceptional stability of the acidic compounds 2 and 19 (100%
remaining compounds after 30 min of incubation) as well as their
potency prompted us to further progress 2 and 19 along the
screening cascade for a more detailed evaluation.
Table 3. Rat Plasma Stability, Microsomal Stability, and log D
of Hydroxamates 12ꢀ16
cmpd
rat plasmaa (%)
rat microsomesb (%)
log D @ 7.4c
12
13
14
15
16
85
96
87
75
1.1
1.8
2.4
3.2
3.3
90
65
85
75
NDd
ND
a % remaining compound after 1 h in rat plasma. b % remaining
c
compound after 30 min in rat microsomes. ACDPhysChem Ver. 12.
d ND: not determined.
less potent in this series, and unfortunately, substitutions around
the pyridine ring were poorly tolerated (data not shown). To
improve the in silico prediction of solubility and lipophilicity of
aryltriflates 2ꢀ22 a trainable model (ACD/Laboratories
PhysChem Ver. 12) incorporating our internal experimental
data was specifically developed. Calculated log D and solubility
values at pH 7.4 are reported (Tables 2ꢀ4).
This class was characterized by extremely low aqueous solu-
bility as in the case of 2-aminothiazole and 1,3,4-thiadiazole
derivatives 4 and 5. While improving water solubility, charged or
polar groups in positions 3 or 4 of the heterocycles compromised
affinity for CXCL8 receptors.13 Similarly, O- or N-containing
aromatic heterocycles (6ꢀ8) showed a moderate reduction of
log P values with about 1-fold increment over the solubility but
paralleled by a slight loss of potency. The trifluoromethyl
substituted compounds 9 and 10, as well as their methyl analogue
11, retained an excellent activity but, as expected, showed
reduced water solubility. The in vitro metabolic fate of com-
pounds 3ꢀ11 was thoroughly investigated, and it was found that
the triflate-substituted phenyl ring was not reactive under the
conditions of the liver microsome assay (data not shown).
This series was also evaluated for cytochrome (CYP) inhibi-
tion in consideration of the known characteristic of nitrogen-
containing heteroaromatic compounds to inhibit CYP enzymes
by direct coordination of the heme iron. As expected, CYP2C9,
CYP2C19, and CYP3A4 were inhibited by the most of the
compounds at the test concentration of 10 μM. The introduction
of methyl or trifluoromethyl groups in the 3 position of the
heterocycle, aimed to increase the steric hindrance and to reduce
First, we estimate the chemical stability of 2 and 19 at different
pH values (3.5, 7.4, and 9) to mimic the physiological environ-
ments of stomach, blood, and intestine, respectively. As expected,
2 and 19 were found stable when subjected to treatment in
aqueous solutions, buffered at pH 3.5 and 7.4 (>99% of remain-
ing compounds after 2 h at 37 °C), whereas they showed an
extremely poor stability at basic pH (average of 30% of remaining
compounds buffered at pH = 9, Supporting Information). Due to
the strong electron withdrawing group (EWG) characteristics,
the introduction of the triflate makes 2 and 19 very acidic, with
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Table 5. Stability of 2 and 19 in Human and Rat Hepatocytesa
pKa values of 4.0 and 4.4, respectively. Additionally, both
compounds showed exceptional rat plasma stability (100%
remaining compounds after 1 h of incubation) as well as high
rat plasma protein binding (Supporting Information). To obtain
an evaluation of their safety potential, the off-target activity was
assessed. The compounds 2 and 19 did not inhibit [3H]-
astemizole binding (100% radioligand binding at 10 μM) in a
whole-cell hERG binding assay and were devoid of inhibition
activity in the five CYP marker enzymes assayed (inhibition <5%
at 10 μM). In a panel of 40 GPCR and ion channel binding
assays, 2 and 19 did not inhibit the reference compound binding
when tested at 10 μM (Ricerca Biosciences LLC). To assess the
sensitivity to the enzymatic chiral inversion, 2 and 19 were
incubated at 10 μM in rat and human hepatocytes. The possible
in vivo interconversion would greatly impair the pharmacological
use of these compounds as CXCL8 inhibitors due to the lack of
activity of the corresponding S-enantiomers.13 We expected that
the introduction of acylsulfonamido in 19 would greatly limit its
potential chiral inversion. In light of these findings, the putative
S-isomers of 2 and 19 were synthesized (21 and 22, respectively).
The parent compounds and their metabolites were analyzed
under chiral conditions, and their corresponding levels (Table 5)
clearly indicate an excellent stability of 19 in both rat and human
hepatocytes.
cmpd 2
human hepatocytes
cmpd 2 cmpd 21
rat hepatocytes
time (min)
cmpd 2
cmpd 21
0
15
2990 ( 8
<LLOQb
21 ( 4
2996 ( 10
2839 ( 12
2541 ( 15
2287 ( 17
2167 ( 22
1946 ( 21
<LLOQ
2932 ( 12
2844 ( 14
2696 ( 16
2620 ( 21
2541 ( 16
117 ( 12
210 ( 7
449 ( 12
664 ( 14
870 ( 17
30
84 ( 8
60
240 ( 16
260 ( 10
330 ( 17
90
120
cmpd 19
human hepatocytes
rat hepatocytes
time (min)
cmpd 2
cmpd 21
cmpd 2
cmpd 21
0
15
<LLOQ
<LLOQ
3 ( 2
<LLOQ
<LLOQ
<LLOQ
2 ( 1
<LLOQ
22 ( 4
5 ( 1
3 ( 2
<LLOQ
7 ( 2
30
31 ( 2
50 ( 2
54 ( 4
56 ( 4
60
15 ( 3
20 ( 2
30 ( 3
Interestingly, as illustrated in Table 5, the clearance of 19 was
proximal to zero and metabolite concentrations were lower than
40 ng/mL in human hepatocytes after 120 min of incubation. On
the contrary, 2 showed higher levels of the corresponding
metabolite 21 in both species. Nonetheless, a net conversion
of 2 to 21 was observed in different proportion 2 h after the
90
3 ( 1
5 ( 2
120
6 ( 2
4 ( 1
a Indicated values ((SD, n = 3) represent the levels (expressed in
ng/mL) of acids 2 and 21 after the incubation of 2 and 19 in human and
rat hepatocytes. LOQ for compounds 2 and 21 was 1 ng/mL in human
and rat hepatocytes. b LLOQ = lower limit of quantification.
Figure 1. Percent of interconversion of 2 into 21 after the incubation of 2 and 19 in rat and human hepatocytes.
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LETTER
incubation of 2 and 19; the conversion was about 30% and 11%
for 2 and 95% and 20% for 19, in rat and human hepatocytes,
respectively (Figure 1).
(3) Youn, B. S.; Mantel, C.; Broxmeyer, H. E. Chemokines, Che-
mokine receptors and hematopoiesis. Immunol. Rev. 2000, 177, 150–
174.
(4) Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert, C. A.; Horuk,
R.; Matsushima, K.; Miller, L. H.; Oppenheim, J. J.; Power, C. A.
International Union of Pharmacology XXII. Nomenclature for chemo-
kine receptors. Pharmacol. Rev. 2000, 52, 145–176.
These observations clearly confirmed the interconversion of 2
into 21 and that the hydrolysis of acylsulfonamido embedded in
19 occurring in hepatocytes is followed by a fast acylation with
inversion of the stereogenic center, leading to 21. In contrast to
the reactive character of aliphatic triflates, no traces of phenol
derivatives were found. Moreover, no traces of 22 were observed,
thus confirming the hypothesis that a reactive ester is a key
intermediate of the enzymatic chiral inversion process. Finally,
the formation of glucuronide metabolites of 2, 19, 21, and 22 was
not observed (Supporting Information).
Overall, in the investigated system, 19 demonstrated a re-
markable in vitro metabolic stability because the formation of its
corresponding carboxylic acids 2 and 21 occurred only in traces.
Similar results were obtained using mouse and dog hepatocytes
(Supporting Information). Then, in virtue of its peculiar in vitro
metabolic profile, 19 was selected for further in vivo investigation.
Pharmacokinetic studies in rat showed a high elimination half-
life (approximately 19 hours) and a clearance of 0.1 mL/(min kg)
after intravenous administration, coherent with the marked
metabolic stability and the strong protein binding.21
(5) Shadidi, K. R. New Drug Targets in Rheumatoid Arthritis:
Focuson Chemokines. BioDrugs 2004, 18, 181–187.
(6) Owen, C. Chemokine receptors in airway disease: which recep-
tors to target?. Pulm. Pharmacol. Ther. 2001, 14, 193–202.
(7) Xia, M.-Q.; Hyman, B. T. Chemokines/chemokine receptors in
the central nervous system and Alzheimer’s disease. J. Neurovirol. 1999,
5, 32–41.
(8) Scheibenbogen, C.; Mohler, T.; Haefele, J.; Hunstein, W.;
Keilholz, U. Serum interleukin-8 (IL-8) is elevated in patients with
metastatic melanoma and correlates with tumour load. Melanoma Res.
1995, 5, 179–181.
(9) Kulke, R.; Bornscheuer, E.; Schluter, C.; Bartels, J.; Rowert, J.;
Sticherling, M.; Christophers, E. The CXC Receptor 2 is overexpressed
in psoriatic epidermis. J. Invest. Dermatol. 1998, 110, 90–94.
(10) White, J. R.; Lee, J. M.; Dede, K.; Imburgia, C. S.; Jurewicz, A. J.;
Chan, G.; Fornwald, J. A.; Dhanak, D.; Christmann, L. T.; Darcy, M. G.;
Widdowson, K. L.; Foley, J. J.; Schmidt, D. B.; Sarau, H. M. Identificaton
of a potent, selective nonpeptide CXCR2 antagonist that inhibits
Interleukin-8-induced neutrophil migration. J. Biol. Chem. 1998, 273,
10095–10098.
(11) Widdowson, K. L.; Elliott, J. D.; Veber, D. F.; Nie, H.; Rutledge,
M. C.; McCleland, B. W.; Xiang, J. N.; Jurewicz, A. J.; Hertzberg, R. P.;
Foley, J. J.; Griswold, D. E.; Martin, L.; Lee, J. M.; White, J. R.; Sarau,
H. M. Evaluation of potent and selective small-molecule antagonists
of the CXCR2 chemokine receptor. J. Med. Chem. 2004, 47, 1319–
1321.
(12) Bertini, R.; Allegretti, M.; Bizzarri, C.; Moriconi, A.; Locati, M.;
Zampella, G.; Cervellera, M. N.; Di Cioccio, V.; Cesta, M. C.; Galliera,
E.; Martinez, F. O.; Di Bitondo, R.; Troiani, G.; Sabbatini, V.; D’
Anniballe, G.; Anacardio, R.; Cutrin, J. C.; Cavalieri, B.; Mainiero, F.;
Strippoli, R.; Villa, P.; Di Girolamo, M.; Martin, F.; Gentile, M.; Santoni,
A.; Corda, D.; Poli, G.; Mantovani, A.; Ghezzi, P.; Colotta, F. Non-
competitive allosteric inhibitors of the inflammatory chemokine recep-
tors CXCR1 and CXCR2: prevention of reperfusion injury. Proc. Natl.
Acad. Sci. 2004, 101, 11791–11796.
(13) Moriconi, A.; Cesta, M. C.; Cervellera, M. N.; Aramini, A.;
Coniglio, S.; Colagioia, S.; Beccari, A. R.; Bizzarri, C.; Cavicchia, M. R.;
Locati, M.; Galliera, E.; Di Benedetto, P.; Vigilante, P.; Bertini, R.;
Allegretti, M. Design of noncompetitive interleukin-8 inhibitors acting
on CXCR1 and CXCR2. J. Med. Chem. 2007, 50, 3984–4002.
(14) Kieser, K. J.; Dong, W. K.; Carlson, K. E.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. Characterization of the pharmacophore
properties of novel selective estrogen receptor downregulators
(SERDs). J. Med. Chem. 2010, 53, 3320–3329.
Additionally, 19 had excellent oral bioavailability in rats (F =
100%, Supporting Information), and it was mostly excreted un-
changed (data not shown).
In summary, this paper reports the drug profiling approach
that guided the characterization of the aryltriflate moiety incor-
porated in the potent CXCR1/CXCR2 clinical candidate 19.
Interestingly, the results herein reported demonstrate for the
first time that, in clear contrast with the strong reactivity of
aliphatic triflates, the aryltriflate group, even if rarely used in
medicinal chemistry, is chemically and biologically stable and
represents a valid choice as EWG substituent of the phenyl ring in
lead optimization studies.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details for the
b
synthesis and characterization of reported compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: +39-0862-338424. Fax: +39-0862-338219. E-mail: ales-
sio.moriconi@dompe.it.
(15) Oh-e, T.; Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-
coupling reaction of organoboron compounds with organic triflates.
J. Org. Chem. 1993, 58, 2201–2208.
(16) Wolfe, P. J.; Buchwald, S. L. Palladium-catalyzed amination of
aryl triflates. J. Org. Chem. 1997, 62, 1264–1267.
’ ABBREVIATIONS
CXCR1, type A CXCL8 receptor; CXCR2, type B CXCL8 receptor;
CYP, cytochrome; EWG, electron withdrawing group; GPCRs,
G-protein coupled receptors; NSAIDs, nonsteroidal antiinflamma-
tory drugs; PMN, neutrophil polymorphonucleate leukocytes;
SAR, structureꢀactivity relationship.
(17) Thomson Reuter Integrity portal at http://www.prous.com/
integrity.
(18) Sanins, S. M.; Adams, W. J.; Kaiser, D. G.; Halstead, G. W.;
Hosley, J.; Barnes, H.; Baillie, T. A. Mechanistic studies on the metabolic
chiral inversion of R-ibuprofen in the rat. Drug Metab. Dispos. 1991,
19, 405–410.
(19) Sanins, S. M.; Adams, W. J.; Kaiser, D. G.; Halstead, G. W.;
Baillie, T. A. Studies on the metabolism and chiral inversion of ibuprofen
in isolated rat hepatocytes. Drug Metab. Dispos. 1990, 18, 527–533.
(20) Flipo, M.; Charton, J.; Hocine, A.; Dassonneville, S.; Deprez,
B.; Deprez-Poulain, R. Hydroxamates: relationships between structure
and plasma stability. J. Med. Chem. 2009, 52, 6790–6802.
’ REFERENCES
(1) Horuk, R. Chemokine receptors. Cytokine Growth Factor Rev.
2001, 12, 313–335.
(2) Gillitzer, R.; Goebeler, M. Chemokines in cutaneous wound
healing. J. Leukocyte Biol. 2001, 69, 513–521.
772
dx.doi.org/10.1021/ml2001533 |ACS Med. Chem. Lett. 2011, 2, 768–773

ACS Medicinal Chemistry Letters
LETTER
(21) Garau, A.; Bertini, R.; Mosca, M.; Bizzarri, C.; Anacardio, R.;
Triulzi, S.; Allegretti, M.; Ghezzi, P.; Villa, P. Development of a
systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its
efficacy in a model of transient cerebral ischemia in the rat. Eur. Cytokine
Network 2006, 17, 35–41.
773
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