II. SAR studies of pyridyl-piperazinyl-piperidine derivatives as CXCR3 chemokine antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.12.114

The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC₅₀ of 0.2 nM.

Full text of DOI:10.1016/j.bmcl.2010.12.114

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1527–1531
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
II. SAR studies of pyridyl–piperazinyl-piperidine derivatives as CXCR3
chemokine antagonists
Yuefei Shao a, , Gopinadhan N. Anilkumar b, , Carolyn DiIanni Carroll a, Guizhen Dong a, James W. Hall III a,
Doug W. Hobbs a, Yueheng Jiang b, Chung-Her Jenh b, Seong Heon Kim b, Joseph A. Kozlowski b,
Brian F. McGuinness a, Stuart B. Rosenblum b, Inna Schulman a, Neng-Yang Shih b, Youheng Shu b,
Michael K. C. Wong b, Wensheng Yu b, Lisa Guise Zawacki a, Qingbei Zeng b
⇑
⇑
a Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA
b Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure–human CXCR3 binding affinity relationship of a series of pyridyl–piperazinyl-piperidine
derivatives was explored. The optimization campaign highlighted the pronounced effect of 20-piperazine
substitution on CXCR3 receptor affinity. Analog 18j, harboring a 20(S)-ethylpiperazine moiety, exhibited a
human CXCR3 IC50 of 0.2 nM.
Received 29 November 2010
Revised 21 December 2010
Accepted 21 December 2010
Available online 28 December 2010
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CXCR3
Chemokine
CXCR3 is a G-protein coupled chemokine receptor which is
predominantly expressed in activated T helper 1 (Th1) cells.1
CXCR3 interacts with three endogenous interferon-inducible che-
mokines (CXCL9, CXCL10, and CXCL11) and has been demon-
strated to play an important role in the Th1 inflammatory
response.2 A search for CXCR3 antagonists has been ignited by
the potential that potent antagonists may have therapeutic bene-
fit in the treatment of multiple sclerosis,3 rheumatoid arthritis,4
allograft rejection,5 psoriasis,6 and tumor metathesis.7 Small mol-
ecule CXCR3 antagonists reported to date contain diverse scaf-
folds;8 including the recently disclosed imidazo-pyrazines,9
ergolines,10 and camphor sulfonamides.11
Synthesis of the analogs generally followed a solution-phase
version of the previously disclosed solid-phase route as outlined
in Scheme 1.12 Nucleophilic aromatic substitution of 2 with an
appropriately substituted Boc-protected piperazine derivative fol-
lowed by ester hydrolysis led to carboxylic acids of structure 3.
HATU-mediated amide formation followed by acid promoted re-
moval of the Boc group, generated intermediates of type 4, which
were converted to general structure 5 via reductive alkylation with
the appropriate Boc-piperidinone derivative. Deprotection of the
piperidine nitrogen and subsequent derivatization afforded the ti-
tle analogs (6a–6q, 7a–7n, 17a–17p, 18a–18l).
We have reported the discovery of a class of CXCR3 antagonists
(1) that contain a piperazinyl-piperidine core flanked by a left side
(as drawn) nicotinamide and a right-side 4-chlorobenzyl group.12
Herein, we report the results of the optimization campaign which
highlights the dramatic effect of the 20-piperazine substitution to
the affinity of this series of CXCR3 antagonists. Furthermore, SAR
exploration of the pendant regions indicates that the hydrogen
bond donor of the alkyl nicotinamide and a one carbon linked aryl
residue to the piperidine are essential for high CXCR3 receptor
affinity in this series.
O
O
O
R1
H
Cl
N
Cl
N
Cl
Cl
a,b
N
c,d
NBoc
HO
MeO
R
R
N
N
N
4
2
3
NH
O
O
R1
Cl
N
R1
Cl
N
N
e
N
d, f
R
R
H
H
N
N
R'
R'
NBoc
Cl
N
N
5
N
Scheme 1. General synthesis of analogs. Reagents and conditions: (a) Boc-
piperazine derivative, K2CO3, DMF, 90 °C; (b) LiOH, MeOH, H2O, rt; (c) amine,
HATU, DIEA, DMF, rt; (d) TFA, DCM, rt; (e) Boc-piperidinone derivative, Na(OAc)3BH,
DCE, rt; (f) 4-chlorobenzaldehyde, Na(OAc)3BH, DCE, rt.
⇑
Corresponding authors.
E-mail addresses: joe.shao@primera-corp.com (Y. Shao), gopinadhan.anilku
mar@Merck.com (G.N. Anilkumar).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.114

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Y. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1527–1531
Table 1
R1
Cl
O
Variation of the right-hand benzyl group
R2
N
H3C
Cl
N
N
H
N
N
R3
N
O
N
Cl
N
H3C
N
Cl
N
H
R4
CH3
N
N
6a-q
7a-n
17a-l
18a-l
N
1
CH3
N
R1
Compds
R1
4-Chlorobenzyl
Furan-2-ylmethyl
Thiophen-2-ylmethyl
Pyrrol-2-ylmethyl
Pyridin-2-ylmethyl
hCXCR3 binding IC50 (nM)
1
32
8100
1980
8060
7990
>10,000
87
The SAR of the benzyl group was further explored with aromatic
and heteroaromatic substitutions (Table 1). Replacement of the
phenyl with unsubstituted aromatic heterocycles reduced binding
affinity (6a–6d). Focus was therefore shifted to substitutions
around the aromatic portion of the benzyl group. Replacement of
the 4-chlorine atom in the lead (1) with a highly polar group such
as 4-methanesulfonyl (6e) substantially reduced affinity. This re-
sult coupled with the poor tolerability of heterocycles, suggested
that the lipophilic right-side interacted with a lipophilic region of
the CXCR3 receptor, and thus further non-polar substitution pat-
terns were explored. Lipophilic substituents such as 4-methyl
(6f) or 4-trifluoromethyl (6g), however, were worse relative to
the initial lead. On the other hand, 2,4-dihalo substitution of the
benzyl group was well tolerated (6h–6j), with the additional
2-halo substitution adding slightly to the overall affinity. Substitu-
tion of the benzylic methylene was investigated to block this
potential metabolic site and moderate the basicity of the piperi-
dine nitrogen for increased absorption. Interestingly, methyl sub-
stitution of the benzylic methylene was stereo-sensitive (6k–6l).
Cyclization from the benzylic carbon to the pendent phenyl ring
(6m–6n) was also tolerated, but did not offer any obvious advan-
tage compared with simple methyl substitution. Benzamide 6o re-
sulted in a seven-fold reduction in affinity compared to compound
1. In general, 4-chlorobenzyl (1) or 2,4-dihalobenzyl (6h–6i) sub-
stitution of the piperidine nitrogen was most preferred. The 4-
chlorobenzyl group was fixed as the benchmark right-hand side
and attention was concentrated on optimizing other regions of
the molecule.
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-(Methylsulfonyl)benzyl
4-Methylbenzyl
4-Trifluoromethyl
4-Chloro-2-fluorobenzyl
2,4-Dichlorobenzyl
4-Fluoro-2-chlorobenzyl
Cl
63
18
17
58
6j
6k
6l
5
CH3
(isomer 1)
Cl
110
CH3
(isomer 2)
Cl
6m
6n
29
35
(isomer 1)
Cl
(isomer 2)
Cl
6o
6p
210
We previously reported that that S-methyl substitution at the
20-position of the piperazine ring resulted in a sufficient affinity
enhancement which then enabled truncation of the high molecular
weight carboxamide tail of the initial screening hit (Table 2; com-
pare unsubstituted 7a and 7c with 2(S)-methyl-substituted 7b and
1).12 This observation prompted an exploration of additional sub-
stitutions of the piperazine and piperidine rings in an attempt to
increase the CXCR3 binding affinity while maintaining the trun-
cated amide.
O
O
>10,000
F
Cl
6q
>10,000
N
Synthesis of the core-modified analogs followed the previously
disclosed route as outlined in Scheme 1.12 The required substituted
piperidine or piperazine intermediates (except those in 7l and 7n)
were available from commercial sources or synthesized according
to known procedures.13 Synthesis of analog 7l is outlined in
Scheme 2. Reaction between Boc-piperazine and 4-chlorob-
enzylpiperidinone in the presence of diethylaluminum cyanide
produced 4-cyano substituted intermediate 8, which was trans-
formed into 4-methyl substituted compound 9 by reaction with
methyl Grignard.14 After removal of the Boc group, fragment 10
was attached to nicotinamide 11 using Buchwald coupling condi-
tions to produce analog 7l. Analog 7n was synthesized from a
piperidine-2,4-dione intermediate as illustrated in Scheme 3. 4-
Chlorobenzylamine was treated with methyl acrylate to produce
secondary amine 12, followed by stirring with diketene to afford
ketone 13. Ring cyclization was achieved by treatment of 13 with
sodium methoxide in methanol and the resultant trione 14 was
O
heated under acidic conditions to remove the acetyl group. The
dione 15 was then coupled with an appropriately substituted inter-
mediate 4 through reductive amination to produce analog 7n.
The beneficial effect of 20-methyl piperizine substitution,
prompted further exploration of methyl substitution throughout
the piperazinyl-piperidine core. While S-methyl substitution on
the 50-position of the piperizine ring was tolerated (Table 2; com-
pare 7g with unsubstituted 7e), 50-methyl substitution with an R
configuration decreased binding affinity six-fold (7h) relative to
the S configuration (7g). The possibility that the conformational ef-
fect of 50-methyl piperazine substitution could be equivalent to the
5-chloro pyridyl was disproven by the weak activity of 5-des-chlo-
ropyridyl racemic compound 7i. Substitution on the core piperi-
dine ring was next investigated. Methyl substitution in the

Y. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1527–1531
1529
Table 2
Effect of substitution on piperazinyl-piperidine core
O
R1
X
R3
N
H
5'
R4
N
N
R6
5"
N
Cl
2'
R2
N
2"
R5
Compds
R1
R2
R3
R4
R5
R6
X
hCXCR3 binding IC50 (nM)
7a
7b
7c
1
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
3,4-Difluorobenzyl
3,4-Difluorobenzyl
Methyl
H
S-Me
H
S-Me
H
S-Me
H
H
H
H
S-Me
H
H
H
H
H
H
H
S-Me
R-Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
Cl
Cl
Cl
40
6
560
32
35
16
Methyl
3,4-Dichlorobenzyl
3,4-Dichlorobenzyl
3,4-Dichlorobenzyl
3,4-Dichlorobenzyl
3,4-Difluorobenzyl
Methyl
39
220
2700
64
31
27
R,S-Me
H
H
H
H
H
R,S-Me
Methyl
H
H
H
H
R,S-Me
H
H
3,4-Dichlorobenzyl
3,4-Difluorobenzyl
Methyl
Carbonyl
S-Me
1400
7000
Carbonyl
methylation of the 400-piperidine carbon was tolerated, but without
a significant change in affinity (7l vs 7e). Hence, methyl substitu-
tion was tolerated in various positions throughout the heterocyclic
core rings but the 20-piperazine position provided the largest aug-
mentation of affinity without a significant increase in the struc-
tural complexity of the targets.
The role of the two basic nitrogens in the core was next ex-
plored with piperazin-2-one 7m and piperidinone 7n. Both lactam
analogs exhibited a substantial drop in activity in relation to their
respective cyclic amine analogs. This observation is consistent with
the lack of activity exhibited by the inverted piperidinyl-piperazine
analog 16a. Attempts were made to revive activity in the ‘reversed’
series by methyl substitution (Table 3; 16b–16d). Interestingly, the
best analog in this series (16d) was substituted with a methyl at
the site analogous to the 20-position of the piperazine in lead struc-
ture 1.
NC
Cl
Cl
O
+
Cl
N
BocN
a
c
BocN
HN
N
N
NH
8
H3C
N
H3C
Cl
b
N
BocN
N
N
9
10
O
Cl
Cl
d
N
H
10
7l
+
Cl
N
11
Cl
Scheme 2. Synthesis of analog 7l. Reagents and conditions: (a) Al(Et)2CN, Ti(OiPr)4,
DCM, rt, 20 h, 41%; (b) CH3MgBr, THF, 60 °C, 2 h, 67%; (c) 6 M aq HCl, EtOAc, rt, 2 h,
93%; (d) Pd(OAc)2, DBBP, Cs2CO3, dioxane, 90 °C, 16 h.
Isosteric replacements for the 5-pyridyl carboxamide (R1, Table
4) were next explored. The methyl ester (17a) and acyclic amidines
(17b, 17c) exhibited weaker activity. A set of ‘reverse’ amides were
prepared.15 Small alkyl amides, such methyl (17d) and cyclopropyl
(17e) amides were equal to or better than the initial lead, but due
to the embedded aminopyridine substructure this series was
deprioritized.
The parent amide (17f) exhibited similar binding affinity to lead
compound 1. Interestingly, an increase in the size and lipophilicity
of the alkyl group improved the affinity (17g–17i). The aromatic
3,4-difluorophenyl amide 17j, however, was equal in affinity to
the methyl amide lead 1. To examine the contribution of the amide
NH group, secondary amides 17k and 17l were prepared. The drop
in affinity of these two derivatives in conjunction with the weak
binding of previously discussed ester 17a confirmed the critical
nature of the proton donor of the amide moiety. In general, simple
alkyl secondary amides displayed the best activity in this series.
Thus, we decided to maintain a small alkyl secondary amide in this
region for the next SAR exploration.
O
NH2
O
O
N
O
a
b
O
N
H
O
Cl
Cl
Cl
12
13
N
N
c
e
d
7n
O
Cl
O
O
O
Cl
O
14
15
Scheme 3. Synthesis of analog 7n. Reagents and conditions: (a) methyl acrylate,
MeOH, 0 °C to rt, 16 h, 98%; (b) diketene, MeOH, 0 °C to rt, 2 h, 100%; (c) NaOMe,
MeOH, rt, 5 h, 96%; (d) 10% aq HCl, EtOH, reflux, 16 h, 85%; (e) 4, Na(OAc)3BH, HOAc,
1,2-dichloroethane, rt, 16 h, 31%.
500-position of the piperidine ring (7j) increased affinity compared
to the unsubstituted analog 7c. This piperidine substitution, how-
ever, increased the stereochemical complexity of the molecule by
the introduction of two new chiral centers which was deemed
undesirable. Methylation of the piperidine0s 200-position was also
tolerated (7k) but this modification also increased the stereochem-
ical complexity without providing any significant benefit. Finally,
Since 20(S)-methyl substitution of the piperazine in 1 enhanced
binding activity, we further explored the SAR at this position (Table
5). Analogs 18a–18d and 18k–18l were prepared from readily
available substituted piperazines13a through the method outlined
in Scheme 1. Analogs 18e–18h were directly derived from
compound 18d (Scheme 4). Reduction of the ester functional group
of 18d with sodium borohydride afforded alcohol analog 18e,

1530
Y. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1527–1531
Table 3
Table 5
Effect of methyl substitution on ‘reversed’ piperidinyl-piperazine analogs
Effect of 2’-substitution on piperazine ring
O
O
R1
R1
Cl
Cl
N
H
N
H
R4
N
N
N
N
N
Cl
Cl
N
R2
R2
R2
N
N
X
Compds R1
R4
H
hCXCR3 binding IC50 (nM)
4500
Compds
R1
R2
H
X
hCXCR3 binding IC50 (nM)
16a
16b
16c
16d
3,4-Dichlorobenzyl
Methyl
Methyl
H
H
H
S-Me 12,500
R-Me
H
7c
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
F
560
32
7350
280
(S)-Methyl
(S)-Ethyl
(S)-Isobutyl
(S)-Phenyl
(R,S)-COOMe
(R,S)-CH2OH
(R,S)-CH2OMe
(R,S)-COOH
R,S-COONHMe
(S)-Ethyl
Methyl
R,S-Me
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
3
260
830
140
910
3100
>50,000
8900
0.3
Table 4
Human CXCR3 binding IC50 of analogs 17a–17l
R1
Cl
N
N
N
Cl
Et
Et
Et
(S)-Ethyl
(S)-Isopropyl
(R,S)-Cyclopropyl
0.2
CH3
N
H
F
23
32
Compds
R1
IC50 (nM)
9
The SAR of the 20-position on the piperazine ring is outlined in
Table 5. The 20(S)-ethyl analog 18a afforded a 10-fold improvement
in affinity (IC50 = 3 nM). Larger alkyl, such as isobutyl (18b) and
phenyl (18c) substitution led to a dramatic drop in binding affinity.
Substitution at the 20-position with a polar substituent such as an
ester, alcohol, ether, carboxylic acid, or carboxamide also signifi-
cantly led to decreased binding affinity (18d–18h). Combination
of the optimized 20-(S)-ethyl-piperazinyl-piperidine core with a
slightly larger ethyl carboxamide R1 substituent produced analogs
18i and 18j which achieved sub-nanomolar CXCR3 receptor bind-
ing affinity. Pairing of a slightly larger 20-(S)-isopropyl- or 20-
(R,S)-cyclopropyl-piperazine with the same ethyl carboxamide R1
substituent (18k, 18l) resulted in a drop in receptor affinity, con-
firming that the 20-(S)-ethyl piperazinyl-piperidine core was fully
optimized.
Representative compounds in all of the series were profiled for
rodent CXCR3 receptor affinity and functional assays.16 Select
mouse and rat CXCR3 affinity data (Table 6) illustrates the nearly
100-fold gain in intrinsic receptor affinity observed for the 20-
substituted compounds 18i and 18j compared with the larger,
unsubstituted structure 7a.
With the SAR for receptor affinity established, attention was
turned to the pharmacokinetics of the lead series. Initial analogs
7a and 7b demonstrated moderate exposure in a rat when orally
dosed (AUC = 920 nM h and 500 nM h, respectively; 10 mpk, 6 h,
O
H3C
1
32
N
H
O
17a
17b
520
80
H3CO
NH
H2N
NH
17c
17d
83
8
H3C
H3C
N
H
H
N
O
H
N
17e
17f
17g
20
39
2.3
O
O
H2N
H3C
O
O
N
H
CH3
17h
17i
5
H3C
N
H
O
2.4
N
H
O
Cl
F
F
N
O
H
17j
22
N
N
O
N
H
N
O
Cl
a
c
N
O
N
18d
17k
17l
900
630
O
O
Cl
N
Cl
N
N
H
N
H
O
N
N
N
Cl
N
Cl
N
X
N
Y
N
18g, Y=COOH
18e, X=CH2OH
18f, X=CH2OCH3
d
b
18h, Y=CONHCH3
which was subsequently transformed into the methyl ether analog
18f by TMSCHN2 treatment. Hydrolysis of ester 18d resulted in the
acid analog 18g, which was used to prepare the carboxamide ana-
log 18h via HATU mediated coupling.
Scheme 4. Synthesis of analogs 18e–18h. Reagents and conditions: (a) NaBH4,
EtOH, 80 °C, 3 h, 85%; (b) TMSCHN2, HBF4, THF, 0 °C, 30 min, 72%; (c) LiOH, H2O/
THF/MeOH, rt, 5 h, 100%; (d) MeNH2, HATU, DIEA, DMF, rt, 16 h, 76%.

Y. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1527–1531
1531
Table 6
Paradis, T. J.; Ogborne, K. T.; Loetscher, M.; Gladue, R. P.; Lin, W.; Boyd, J. G.;
Moser, B.; Wood, D. E.; Sahagan, B. G.; Neote, K. J. Exp. Med. 1998, 187, 2009; (c)
Turner, J. E.; Steinmetz, O. M.; Stahl, R. A.; Panzer, U. Mini-Rev. Med. Chem. 2007,
7, 1089.
PK profile of lead CXCR3 antagonists
Compds Mouse CXCR3 binding
IC50 (nM)
Rat CXCR3 binding
IC50 (nM)
Rat AUCa
(nM h)
3. (a) Szczucin´ ski, A.; Losy, J. Acta Neurol. Scand. 2007, 115, 137; (b) Sindern, E.;
Patzhold, T.; Ossege, L. M.; Gisevius, A.; Malin, J.-P. J. Neuroimmunol. 2002, 131,
186.
4. Patel, D. D.; Zachariah, J. P.; Whichard, L. P. Clin. Immunol. 2001, 98, 39.
5. (a) Rosenblum, J. M.; Zhang, Q.-W.; Siu, G.; Collins, T. L.; Sullivan, T.; Dairaghi,
D. J.; Medina, J. C.; Fairchild, R. L. Transplantation 2009, 87, 360; (b) Bastani, S.;
Sherman, W.; Schnickel, G. T.; Hsieh, G. R.; Bhatia, R.; Fishbein, M. C.; Ardehali,
A. Transplantation 2009, 88, 995.
7a
7b
18i
18j
84
97
920
500
410
950
6.7
0.5
1.1
9.9
1.2
1.6
a
PO, 10 mpk, 6 h, 0.4% MC.
6. (a) Rottman, J. B.; Smith, T. L.; Ganley, K. G.; Kikuchi, T.; Krueger, J. G. Lab. Invest.
2001, 81, 335; (b) Homey, B. Curr. Drug Targets Inflamm. Allergy 2004, 3, 169.
7. Pradelli, E.; Karimdjee-Soilihi, B.; Michiels, J.-F.; Ricci, J.-E.; Millet, M.-A.;
Vandenbos, F.; Sullivan, T. J.; Collins, T. L.; Johnson, M. G.; Medina, J. C.;
Kleinerman, E. S.; Schmid-Alliana, A.; Schmid-Antomarchi, H. Int. J. Cancer
2009, 125, 2586.
MC).17 The smaller, more active analogs 18i and 18j maintained
comparable exposure levels (AUC = 410 nM h and 950 nM h,
respectively). Hence, truncation of the R1 carboxamide substituent
was not sufficient to enhance the rat PK profile of this series of
CXCR3 antagonists.
8. Wijtmans, M.; Verzijl, D.; Leurs, R.; de Esch, I. J. P.; Smit, M. J. ChemMedChem
2008, 3, 861.
In summary, modifications were made throughout the piperaz-
inyl-piperidine core of the CXCR3 antagonist 1. While tolerated,
most of the pyridyl carboxamide or benzyl substitutions did not
enhance binding affinity toward the CXCR3 receptor. In contrast,
changes to the 20-position of the piperazine had a strong influence
on receptor binding. A modest increase in the size of the alkyl
group at the 20-position of the piperazine ring from methyl to ethyl,
improved binding affinity significantly, resulting in the first re-
ported sub-nanomolar (IC50) CXCR3 receptor antagonists. Hence,
the 20-position of the piperazine ring is an important pharmaco-
phore element in the interaction of the current lead molecules
18i and 18j with the CXCR3 receptor. Further optimization efforts
in this series will be reported in separate publications.
9. Du, X.; Gustin, D. J.; Chen, X.; Duquette, J.; McGee, L. R.; Wang, Z.; Ebsworth, K.;
Henne, K.; Lemon, B.; Ma, J.; Miao, S.; Sabalan, E.; Sullivan, T. J.; Tonn, G.;
Collins, T. L.; Medina, J. C. Bioorg. Med. Chem. Lett. 2009, 19, 5200.
10. Thoma, G.; Baenteli, R.; Lewis, I.; Wagner, T.; Oberer, L.; Blum, W.; Glickman, F.;
Streiff, M. B.; Zerwes, H.-G. Bioorg. Med. Chem. Lett. 2009, 19, 6185.
11. Wang, Y.; Busch-Petersen, J.; Wang, F.; Kiesow, T. J.; Graybill, T. L.; Jin, J.; Yang,
Z.; Foley, J. J.; Hunsberger, G. E.; Schmidt, D. B.; Sarau, H. M.; Capper-Spudich, E.
A.; Wu, Z.; Fisher, L. S.; McQueney, M. S.; Rivero, R. A.; Widdowson, K. L. Bioorg.
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References and notes
15. Analogs 17e–17i were synthesized as previously described.12
16. Representative compounds 6k, 6l, 7b, 17h and 17i showed functional
anatagonism in CXCR3 mediated chemotaxis assays. For example compound
7b showed IC50 of 23 nM in IP-10 induced hCXCR3 chemotaxis.
17. Sprague–Dawly rat PK of compound 7b was determined: AUC (PO, 5 mpk,
24 h) = 1100 nM h, T1/2 = 6.8 h, Vd[ss] = 17.6 L/kg, and CL = 32.6 mL/min/kg.
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Additionally, CYP 2D6, 3A4 and 2C19 inhibition (IC50) was >10 lM.