Reduced cardiac side-effect potential by introduction of polar groups: Discovery of NIBR-1282, an orally bioavailable CCR5 antagonist which is active in vivo

Article abstract of DOI:10.1016/j.bmcl.2008.01.108

Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduction system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of CsA led to significant prolongation of kidney allograft survival in cynomolgus monkeys.

Full text of DOI:10.1016/j.bmcl.2008.01.108

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 2000–2005
Reduced cardiac side-effect potential by introduction
of polar groups: Discovery of NIBR-1282, an orally
bioavailable CCR5 antagonist which is active in vivo
Gebhard Thoma,* Christian Beerli, Marc Bigaud, Christian Bruns, Nigel G. Cooke,
Markus B. Streiff and Hans-Guenter Zerwes
Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4002 Basel, Switzerland
Received 19 December 2007; revised 26 January 2008; accepted 29 January 2008
Available online 2 February 2008
Abstract—Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduc-
tion system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit
heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of CsA led to significant prolonga-
tion of kidney allograft survival in cynomolgus monkeys.
ꢀ 2008 Elsevier Ltd. All rights reserved.
The chemokine receptor CCR5 interacts with several
high affinity ligands (i.e., RANTES, MIP-1a, MIP-1b,
MCP-2) and plays an important role in inflammatory
and autoimmune disorders by affecting the trafficking
of effector T cells and monocytes to diseased tissues.1
In addition, CCR5 can function as a co-receptor for
macrophage-infecting strains of HIV. A mutation in
the human CCR5 gene (i.e., the CCR5D32 mutation)
which leads to CCR5 deficiency in homozygous carriers
confers protection against HIV infection without being
associated with increased morbidity.2,3 Furthermore, it
has been demonstrated that renal transplant recipients
homozygous for CCR5D32 show significantly prolonged
graft survival compared to CCR5 wild-type or heterozy-
gous individuals.4,5 As all patients have received full
immunosuppressive treatment this finding indicates that
a CCR5 inhibitor on top of standard medication may re-
sult in an additional beneficial effect.
react with the cynomolgus monkey (cyno) receptor.
Compound 1 (Table 1) had good PK properties in cynos
and an overall favorable profile making it a potential
candidate for in vivo profiling in transplantation and
other disease models. However, to our disappointment
we found that most of these compounds even at concen-
trations below 1 lM showed adverse cardiac side-effects
(such as action potential duration prolongation, trian-
gulation, reverse use dependence, and instability) in an
ex vivo isolated rabbit heart model (SCREENIT).8
Antagonist 1 was safe up to 1.5 lM but this was consid-
ered insufficient for a development candidate in man.
Therefore, we decided not to evaluate compound 1 fur-
ther in cynos but rather to improve the cardiac safety
profile.9
Here we disclose NIBR-1282 (=18), a selective, compet-
itive CCR5 antagonist with good oral bioavailability in
cynos and dogs, which did not show any potential for
cardiac side-effects even at 10 lM. The compound was
discovered by modifying the distribution of polar
groups within our series. In combination with a sub-
therapeutic dose of cyclosporine A it was efficacious in
a life-supporting kidney transplantation model in cynos.
Recently, we have reported on the SAR of a new series
of highly potent and selective competitive CCR5 antag-
onists.6 While all compounds are inactive on both rat
and murine CCR5, this series includes examples, in con-
trast to CCR5 inhibitors from other series,7 which cross-
Several representatives of our series (1–8) were tested in
the SCREENIT model (Table 1). With the exception of
1, all compounds with polar groups in the right-hand
portion but lacking polarity in the left-hand portion
Keywords: Chemokines; Chemokine receptors; CCR5; Cardiac side-
effects; hERG.
*
Corresponding author. Tel.: +41 61 3243342; fax: +41 61 3246735;
e-mail: gebhard.thoma@novartis.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.108

G. Thoma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2000–2005
2001
Table 1. CCR5 antagonists
Compound
Binding (CCR5)
a
hu/cy IC50 [nM]
Rabbit heart model
safe up tob [lM]
Binding (hERG)c
clogD
IC50 [lM]
O
N
N
N
N
N
1
2.9/12
1.0/2.2
2.3/1.1
3.3/3.4
2.0/5.1
2.6/0.7
1.4/3.0
0.6/2.8
0.5/1.1
1.5
1.2
2.3
2.9
3.8
2.5
2.4
4.9
4.8
1.9
4.5
+
N O
N
O
N
2
<0.5
<0.5
<0.5
<0.5
1.0
n.t.
0.57
n.t.
0.55
0.15
0.67
1.3
N
N
N
O
3
N
N
N
N
N
O
4
N
+
N O
O
5
N
N
N
O
+
N O
6
N
N
N
O
7
1.5
N
N
N
O
NC
8
1.0
N
N
N
+
N O
O
9
<0.5
n.t.
N
N
N
N
(continued on next page)

2002
G. Thoma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2000–2005
Table 1 (continued)
Compound
Binding (CCR5)
a
hu/cy IC50 [nM]
Rabbit heart model
safe up tob [lM]
Binding (hERG)c
clogD
IC50 [lM]
O
N
N
N
10
11
2.0/9.8
1.3/3.6
6.5/39
<0.5
n.t.
n.t.
0.41
4.5
N
O
1.0
4.2
2.4
N
N
N
N
O
O
O
12
13
<0.5
N
N
N
N
N
N
N
N
N
N
Cl
0.8/3.2
<0.5
2.0
3.5
Cl
N
N
N
N
Cl
14
15
16
17
18
1.0/4.2
1.0
1.0
1.0
5.0
>10
4.4
2.3
1.7
3.0
1.4
1.7
Cl
+
N
O
O
1.8/12
n.t.
N
N
N
N
+
N O
O
0.9/0.8
1.7/107
5.1/8.1
>30
12.2
>30
N
N
N
N
O
N
N
N
N
O
N
+
S
N O
N
N
N
+
N O
N
a Average of at least three independent measurements; for details on the assays see Ref. 7.
b See Ref. 8 for details on the SCREENIT model which measures adverse cardiac side-effects such as action potential duration prolongation,
triangulation, reverse use dependence and instability.
c Test compounds compete for [3H] dofetilide binding to a preparation of HEK-293 cell membranes stably transfected with hERG channels.

G. Thoma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2000–2005
2003
(2–5) showed adverse effects below 0.5 lM whereas com-
pounds 6 and 7 without any polar groups appeared to be
superior. Compound 8 with polar groups in both por-
tions also showed an improved profile. To further ex-
plore the effects of polarity and distribution of polar
groups on the cardiac side-effect potential, we prepared
highly potent antagonists (9–18, Table 1) according to
the previously established procedures,6 and tested them
in the SCREENIT model. Compounds 9–11 with polar
groups in the left-hand portion but lacking polarity in
the right-hand portion showed adverse effects at low
concentrations mirroring the properties of compounds
2–5 with a polar group only in the right-hand portion.
Compounds 12–18 with polar groups in both the left-
and right-hand portion gave mixed but best results.
Two representatives (12, 13) showed adverse effects be-
low 0.5 lM whereas compounds 14–16 were safe up to
1 lM. Antagonist 17 was safe up to 5 lM but showed
unsatisfying cross-reactivity with cyno CCR5. Com-
pound 18 (NIBR-1282) was safe even at 10 lM and
was selected for further profiling both in vitro and
in vivo. Most compounds were also tested in a biochem-
ical assay measuring competitive inhibition of [3H] dof-
etilide binding to a preparation of HEK-293 cell
membranes stably transfected with hERG channels. As
the SCREENIT model is not solely dependent on hERG
inhibition, it is not unexpected that some compounds
showed a poor correlation between ex vivo model and
hERG binding assay (e.g., 6, 13, 16).10
NIBR-1282 was prepared in seven steps in an overall
yield of 16.6% (Scheme 1). Intermediate 19 was obtained
from aniline (20) and the protected piperidone 21.
Aminoheteroarylation with bromopyridine 22 gave 23,
which was deprotected (! 24), reacted with 21 in the
presence of Ti(O-i-Pr)4 and, subsequently, with
Et2AlCN to give 25. Treatment with CH3MgBr gave
26 which upon removal of the protecting group gave
27. Condensation of 27 with 28 yielded the final com-
pound 18 = NIBR-1282.11
NIBR-1282 was tested in a series of CCR5-dependent
in vitro assays (see Table 2). It was highly potent in
radioligand binding assays using membranes from
Br
N
22, 1.0 equiv.
a)
+
NBoc
N
H
NBoc
O
b)
41%
88%
NH2
21
20, 1.1 eqiv.
19
O
NBoc
c)
21, 1.1 equiv.
N
NBoc
N
NH
d)
94%
77%
N
N
23
24
N
N
e)
84%
f)
N
NBoc
N
N
NBoc
(quant)
N
N
25
26
O
+ O
N
HO
O
N
28, 1.1 equiv.
N
N
NH
N
N
g)
N+ O
76%
N
N
27
18= GT-1282
Scheme 1. Reagents and conditions: (a) NaBH(OAc)3, AcOH (CH2Cl)2, 25 ꢁC, 16 h; (b) Pd(OAc)2 (3 mol%), xantphos (4.5 mol%), NaOt-Bu
(4 equiv), toluene, 110 ꢁC, 16 h; (c) TFA/CH2Cl2/H2O (8:5:1), 25 ꢁC, 2 h; (d) Ti(O-i-Pr)4 (1.1 equiv) (CH2Cl)2, 25 ꢁC, 16 h, then Et2AlCN (2.2 equiv
1.0 M solution in toluene), 25 ꢁC, 4 h; (e) CH3MgBr (5.0 equiv 3.0 M solution in ether), THF; (f) TFA/CH2Cl2/H2O (8:5:1), 25 ꢁC, 2 h, HBTU
(1.1 equiv), DMF/EtN(i-Pr)2 (5:3).

2004
G. Thoma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2000–2005
CHO cells transfected with human or cyno CCR5 and
human MIP-1a as ligand but inactive on murine
CCR5. In a functional assay it effectively inhibited ago-
nist-induced Ca2+-mobilization. Compound NIBR-1282
was also highly potent in CCR5 mediated migration as-
says with CCR5 transfected L1.2 cells. The Schild–Gad-
dum analysis with NIBR-1282 using the radioligand
binding assay indicated a competitive mode of inhibi-
tion.12 The compound did not inhibit cytochrome
P450 enzymes with IC50 values below 5300 nM indicat-
ing a low potential for drug–drug interactions which is
particularly important for an application in transplanta-
tion where generally several immunosuppressive drugs
are being applied at the same time. The compound
was highly stable when incubated with liver microsomes
(low intrinsic clearance), exhibited excellent aqueous sol-
ubility and was only weakly bound by human and rat
plasma proteins. NIBR-1282 is a selective antagonist
of CCR5 and did not inhibit other chemokine receptors
(CCR1, CCR2, CCR3, CCR4, CCR6, CCR7, CXCR1,
CXCR2, CXCR3, CXCR4, CXCR6) when tested at
concentrations up to 1 lM. Furthermore, screening
against a broad panel of non-chemokine GPCRs
(including muscarinic acetylcholine receptors) and vari-
ous ion channels did not show inhibition of any of these
receptors or channels at 1 lM.
The oral exposure of NIBR-1282 in rats was not favor-
able (Table 3). However, satisfactory PK profiles were
obtained both in cynos (F 43%; MRT 6 h) and dogs (F
56%; MRT 8 h) making NIBR-1282 an interesting can-
didate for further in vivo evaluation.
NIBR-1282 was tested in a model of life-supporting kid-
ney transplantation in cynomolgus monkeys.13 In this
model, untreated recipients rejected their graft within
7–10 days (entry 1 in Table 4) and high doses of cyclo-
sporine A (CsA; 100 mg/kg d, po) were required to
achieve long term survival (>100 q.d.). A lower dose
of CsA (20 mg/kg q.d., po) did not affect graft survival
(entry 2 in Table 4). NIBR-1282 as monotherapy was
also non-efficacious (entry 3 in Table 4). However, the
combination of non-efficacious doses of CsA and
NIBR-1282 led to statistically significant prolongation
of graft survival (entries 4, 5 in Table 4; p < 0.05).
Importantly, combining NIBR-1282 and CsA did not re-
sult in significant increase in CsA exposure, as revealed
by monitoring the CsA blood levels that all varied with-
in 30–140 ng/ml, strongly indicating that the efficacy of
the CsA/NIBR-1282 combination was due to a pharma-
codynamic interaction between both drugs rather than a
pharmacokinetic interaction.
Table 2. Properties of compound NIBR-1282 (18)
Assay
Result
hu CCR5 (binding)
cy CCR5 (binding)
MIP-1a-induced
Ca2+-mobilization (hu)
MIP-1a-induced
Ca2+-migration (cy)
MIP-1a-induced migration
of transfectants (hu)
CYP1A2
IC50 = 5.1 1.7 nM
IC50 = 8.1 1.5 nM
IC50 = 43.6 3.2 nM
In conclusion, NIBR-1282 is a selective, competitive
CCR5 antagonist with promising oral bioavailability
in dogs and cynos. It did not show adverse effects when
tested in an isolated rabbit heart ex vivo model. It was
discovered modifying both the polarity (logD) and the
distribution of polar groups within a series of potent
CCR5 antagonists which were very likely to adversely
affect the conduction system in the heart. Administra-
tion of NIBR-1282 in combination with a non-effica-
cious dose of CsA led to significant prolongation of
IC50 = 64 7.7 nM
IC50 = 16.2 3.1 nM
IC50 > 10,000 nM
IC50 > 10,000 nM
IC50 > 10,000 nM
IC50 > 10,000 nM
IC50 = 5300 nM
IC50 > 30,000 nM
23% inh. at 22,000 nM
8.3, 5.5
CYP2C9
CYP2C19
CYP2D6
CYP3A4
hERG (binding)
hERG (patch clamp)
pKa
logP
2.2
Table 4. NIBR-1282 tested in a kidney transplantation model in
cynomolgus monkeys13
logD (pH 6.8)
Intrinsic clearance (hu)
Intrinsic clearance (rat)
Solubility (water)
Solubility (pH 7.4)
Caco2
0.8
<15 lL minꢀ1 mgꢀ1
<15 lL minꢀ1 mgꢀ1
1.0 g/L
Entry
NIBR-1282
(mg/kg)
CsA
(mg/kg, po)
Graft survival
(days)
1
2
3
4
5
—
—
—
20 q.d.
—
7–10a
>12.5 g/L
Efflux
7, 7, 7, 7, 11
6, 6
PAP–BL: 4 · 10ꢀ5 cm/min
PBL–AP: 65 · 10ꢀ5 cm/min
Free fraction: 62%
Free fraction: 48%
20 b.i.d.; sc
20 b.i.d.; sc
40 q.d.; po
20 q.d.
20 q.d.
8, 37, 66, >100
9, 20, 36, 39
Protein binding (hu)
Protein binding (rat)
a Range.
Table 3. Pharmacokinetic parameters of NIBR-1282 (18) following po administration
b
Cmax [ng/ml]
Species
AUCa [ng/ml h]
Tmax [h]
T1/2 [h]
Fd [%]
Rat
Cyno
Dog
41 9.2
503 208
278 79
5.8 1.7
93 38
84 35
0.4–4.0c
0.5–4.0c
0.9 0.6
8.1
6.3
7.9
22
43
56
a Area under the curve normalized to a dose of 1 mg/kg.
b Maximal concentration normalized to a dose of 1 mg/kg.
c Range.
d Oral bioavailability obtained from ratio AUC (oral administration)/AUC (iv administration).

G. Thoma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2000–2005
2005
5. For reviews on the role of chemokines and their receptors
in transplant rejection see (a) DeVries, M. E.; Hosiawa, K.
A.; Cameron, C. M.; Bosinger, S. E.; Persad, D.; Kelvin,
A. A.; Coombs, J. C.; Wang, H.; Zhong, R.; Cameron, M.
J.; Kelvin, D. J. Semin. Immunol. 2003, 15, 33; (b) Nelson,
P. J.; Krensky, A. M. Immunity 2001, 14, 377; (c)
Hancock, W. W.; Wang, L.; Ye, Q.; Han, R.; Lee, I.
Curr. Opin. Immunol. 2003, 15, 479.
6. Thoma, G.; Nuninger, F.; Schaefer, M.; Akyel, K. G.;
Albert, R.; Beerli, C.; Bruns, C.; Francotte, E.; Luyten,
M.; MacKenzie, D.; Oberer, L.; Streiff, M. B.; Wagner, T.;
Walter, H.; Weckbecker, G.; Zerwes, H.-G. J. Med. Chem.
2004, 47, 1939.
kidney allograft survival in cynomolgus monkeys. Inhi-
bition of CCR5 may offer new therapeutic opportunities
for transplant patients.14
Acknowledgment
We thank the members of the Novartis non-human pri-
mate transplantation group for their valuable
contributions.
7. Strizki, J. M.; Xu, S.; Wagner, N. E.; Wojcik, L.; Liu, J.;
Hou, Y.; Endres, M.; Palani, A.; Shapiro, S.; Clader, J.
W.; Greenlee, W. J.; Tagat, J. R.; McCombie, S.; Cox, K.;
Fawzi, Ahmad B.; Chou, C.-C.; Pugliese-Sivo, C.; Davies,
L.; Moreno, M. E.; Ho, D. D.; Trkola, A.; Stoddart, C.
A.; Moore, J. P.; Reyes, G. R.; Baroudy, B. M. Proc. Natl.
Acad. Sci. U.S.A. 2001, 98, 12718.
8. (a) Valentin, J.-P.; Hoffmann, P.; De Clerck, F.; Ham-
mond, T. G.; Hondeghem, L. J. Pharmacol. Toxicol.
Methods 2004, 49, 171; (b) Hondeghem, L. M.; Hoffmann,
P. J. Cardiovasc. Pharmacol. 2003, 41, 14.
9. (a) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G.
J. Med. Chem. 2006, 49, 5029; (b) Price, D. A.; Armour,
D.; De Groot, M.; Leishman, D.; Napier, C.; Perros, M.;
Stammen, B. L.; Wood, A. Bioorg. Med. Chem. Lett. 2006,
16, 4633.
References and notes
1. (a) Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert,
C. A.; Horuk, R.; Matsushima, K.; Miller, L. H.;
Oppenheim, J. J.; Power, C. A. Pharmacol. Rev. 2000,
52, 145; (b) Moser, B.; Loetscher, P. Nat. Immunol. 2001,
2, 123; (c) Loetscher, P.; Uguccioni, M.; Bordoli, L.;
Baggiolini, M.; Moser, B.; Chizzolini, C.; Dayer, J. M.
Nature 1998, 391, 344; (d) Kunkel, E. J.; Boisvert, J.;
Murphy, K.; Vierra, M. A.; Genovese, M. C.; Wardlaw,
A. J.; Greenberg, H. B.; Hodge, M. R.; Wu, L.; Butcher,
E. C.; Campbell, J. J. Am. J. Pathol. 2002, 160, 347.
2. Berger, E. A.; Murphy, P. M.; Farber, J. M. Annu. Rev.
Immunol. 1999, 17, 657.
3. For small molecule CCR5 antagonists as potential anti-
HIV agents see (a) Gao, Z.; Metz, W. A. Chem. Rev. 2003,
103, 3733; (b) Kazmierski, W.; Bifulco, N.; Yang, H.;
Boone, L.; DeAnda, F.; Watson, C.; Kenakin, T. Bioorg.
Med. Chem. 2003, 11, 2663, 4155; (c) Palani, A.; Tagat, J.
R. J. Med. Chem. 2006, 49, 2851; (d) Mills, S. G.;
DeMartino, J. A. Curr. Top. Med. Chem. 2004, 4, 1017; (e)
Maeda, K.; Nakata, H.; Ogata, H.; Koh, Y.; Miyakawa,
T.; Mitsuya, H. Curr. Opin. Pharmacol. 2004, 4, 447; (f)
Wood, A.; Armour, D. Prog. Med. Chem. 2005, 43, 239;
(g) Cumming, J. G.; Brown, S. J.; Cooper, A. E.; Faull, A.
W.; Flynn, A. P.; Grime, K.; Oldfield, J.; Shaw, J. S.;
Shepherd, E.; Tucker, H.; Whittaker, D. Bioorg. Med.
Chem. Lett. 2006, 16, 3533; (h) Habashita, H.; Kokubo,
M.; Hamano, S.-I.; Hamanaka, N.; Toda, M.; Shibayama,
S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.;
Mitsuya, H. J. Med. Chem. 2006, 49, 4140; (i) Imamura,
S.; Ichikawa, T.; Nishikawa, Y.; Kanzaki, N.; Takashima,
K.; Niwa, S.; Iizawa, Y.; Baba, M.; Sugihara, Y. J. Med.
Chem. 2006, 49, 2784; (j) Nishizawa, R.; Nishiyama, T.;
Hisaichi, K.; Matsunaga, N.; Minamoto, C.; Habashita,
H.; Takaoka, Y.; Toda, M.; Shibayama, S.; Tada, H.;
Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H.
Bioorg. Med. Chem. Lett. 2007, 17, 727; (k) Lu, S.-F.;
Chen, B.; Davey, D.; Dunning, L.; Jaroch, S.; May, K.;
Onuffer, J.; Phillips, G.; Subramanyam, B.; Tseng, J.-L.;
Wei, R. G.; Wei, M.; Ye, B. Bioorg. Med. Chem. Lett.
2007, 17, 1833.
10. For models of the hERG channel to predict how
compounds might bind see (a) Cavalli, A.; Poluzzi, E.;
De Ponti, F.; Recanatini, M. J. Med. Chem. 2002, 45,
3844; (b) Perry, M.; de Groot, M. J.; Helliwell, R.;
Leishman, D.; Tristani-Firouzi, M.; Sanguinetti, M. C.;
Mitcheson, J. Mol. Pharmacol. 2004, 66, 240.
1
11. Analytical data for NIBR-1282. H NMR (CDCl3, 20 ꢁC)
d = 8.14 (1H, d), 8.11 (1H, d), 8.11 (1H, d), 7.38 (2H, t),
7.20 (1H, t), 7.11 (1H, dd), 6.98 (1H, d), 6.96 (2H, d), 6.94
(1H, m), 4.04 (1H, m), 3.82 (1H, m), 3.43 (1H, m), 3.22
(1H, m), 2.99 (1H, m), 2.94 (1H, m), 2.85 (1H, m), 2.38
(3H, s), 2.28 (1H, t), 2.26 (1H, t), 2.24 (3H, s), 2.02 (1H,
m), 1.98 (1H, m), 1.94 (1H, m), 1.75 (1H, m), 1.43 (1H, m),
1.41 (1H, m), 1.35 (1H, m), 1.26 (1H, m), 0.97 (3H, s),
HRMS/ESI C30H38N5O2 Calcd: 500.3026. Found:
500.3028.
12. Gaddum, J. H. Pharmacol. Rev. 1957, 9, 211.
13. Details on the transplantation experiments will be pub-
lished elsewhere. For details on the model see Schuler, W.;
Bigaud, M.; Brinkmann, V.; di Padova, F.; Geisse, S.;
Gram, H.; Hungerford, V.; Kleuser, B.; Kristofic, C.;
Menninger, K.; Tees, R.; Wieczorek, G.; Wilt, C.; Wio-
land, C.; Zurini, M. Transplantation 2004, 77, 717.
14. Very recently, a study of the role of CCR5 blockade on the
modulation of inflammation and alloimmunity in primates
has been published Schroeder, C.; Pierson, R. N.; Nguyen,
B.-N. H.; Kawka, D. W.; Peterson, L. B.; Wu, G.; Zhang,
T.; Springer, M. S.; Siciliano, S. J.; Iliff, S.; Ayala, J. M.;
Lu, M.; Mudgett, J. S.; Kathy Lyons, K.; Mills, S. G.;
Miller, G. G.; Singer, I. I.; Azimzadeh, A. M.; DeMartino,
J. A. J. Immunol. 2007, 179, 2289.
4. (a) Fischereder, M.; Luckow, B.; Hocher, B.; Wuthrich, R.
P.; Rothenpieler, U.; Schneeberger, H.; Panzer, U.; Stahl,
R. A.; Hauser, I. A.; Budde, K.; Neumayer, H.; Kramer,
B. K.; Land, W.; Schlondorff, D. Lancet 2001, 357, 1758;
(b) Strieter, R. M.; Belperio, J. A. Lancet 2001, 357, 1725.