Synthesis and SAR of 1,2,3,4-Tetrahydroisoquinoline-Based CXCR4 Antagonists

Article abstract of DOI:10.1021/acsmedchemlett.7b00381

CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison to normal cells, cancer cells overexpress CXCR4, which correlates with cancer cell metastasis, angiogenesis, and tumor growth. CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12-mediated pro-survival signaling and by inhibiting chemotaxis. Herein, we describe a series of CXCR4 antagonists that are derived from (S)-5,6,7,8-tetrahydroquinolin-8-amine that has prevailed in the literature. This series removes the rigidity and chirality of the tetrahydroquinoline providing 2-(aminomethyl)pyridine analogs, which are more readily accessible and exhibit improved liver microsomal stability. The medicinal chemistry strategy and biological properties are described.

Full text of DOI:10.1021/acsmedchemlett.7b00381

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Letter
Synthesis and SAR of 1,2,3,4-
Tetrahydroisoquinoline Based CXCR4 Antagonists
Robert J. Wilson, Edgars Jecs, Eric J Miller, Huy Hoang Nguyen, Yesim Altas Tahirovic,
Valarie M Truax, Michelle B. Kim, Katie M. Kuo, Tao Wang, Chi Shing Sum, Mary Ellen
Cvijic, Anthony A. Paiva, Gretchen M Schroeder, Lawrence J Wilson, and Dennis C. Liotta
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00381 • Publication Date (Web): 08 Dec 2017
Downloaded from http://pubs.acs.org on December 8, 2017
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Synthesis and SAR of 1,2,3,4-Tetrahydroisoquinoline Based CXCR4
Antagonists
Robert J. Wilson;§ Edgars Jecs;§ Eric J. Miller;§ Huy H. Nguyen;§ Yesim A. Tahirovic;§ Valarie M. Truax;§ Michelle B.
Kim;§ Katie M. Kuo;§ Tao Wang;‡ Chi Shing Sum;‡ Mary E. Cvijic;‡ Anthony A. Paiva; ‡ Gretchen M. Schroeder;‡ Lawꢀ
rence J. Wilson;§* Dennis C. Liotta§ *
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§Department of Chemistry, Emory University, 1515 Dickey Drive NE, Atlanta, GA 30322, United States
‡Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States
KEYWORDS: CXCR4, GPCR, antagonist, chemokine, anti-cancer, tetrahydroisoquinoline, muscarinic, biotransformation
ABSTRACT: CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison
to normal cells, cancer cells overꢀexpress CXCR4, which correlates with cancer cell metastasis, angiogenesis and tumor growth.
CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12ꢀmediated proꢀsurvival signalꢀ
ing and by inhibiting chemotaxis. Herein, we describe a series of CXCR4 antagonists that are derived from (S)ꢀ5,6,7,8ꢀ
tetrahydroquinolinꢀ8ꢀamine that has prevailed in the literature. This series removes the rigidity and chirality of the tetrahydroquinoꢀ
line providing 2ꢀ(aminomethyl)pyridine analogs, which are more readily accessible and exhibit improved liver microsomal stabilꢀ
ity.
The
medicinal
chemistry
strategy
and
biological
properties
are
described.
Chemokines and chemokine receptors are essential to immune
cell trafficking.1 The human chemokine system contains four
types of ligands differentiated by their cysteine residue pattern
at the amino termini.2 Of particular interest is the CꢀXꢀC motif
containing chemokine receptor type 4 (CXCR4). CXCR4 is a
seven transmembrane G proteinꢀcoupled receptor (GPCR).3 In
normal embryonic and adult tissue, CXCR4 expression is priꢀ
marily associated with hematopoietic and immune systems;
however, it can be found in several other tissues including the
thymus, brain and small intestine. When CXCR4 is bound to
its specific natural ligand CXCL12 (also known as stromal cell
derived factor 1, SDFꢀ1), downstream signals mediated by
heterotrimeric G proteins trigger various cellular responses
including increased intracellular calcium flux, gene transcripꢀ
tion, chemotaxis, cell survival and proliferation.1 CXCR4
stands as the most widely overꢀexpressed chemokine receptor
in human tumor cells.4ꢀ7 In several types of cancer, CXCR4
activation stimulates proliferation, angiogenesis, migration,
adhesion, invasion, metastasis and survival.8 Because cancer
cells utilize the CXCR4/CXCL12 mechanism for survival,
metastasis and immune evasion, identification of new and
effective small molecule CXCR4 inhibitors would be benefiꢀ
cial.
Figure 1. Literature Examples of Small Molecule CXCR4
Antagonists.
Several small molecule CXCR4 antagonists exemplified by
AMD3100 (Plerixafor, Mozobil),9 AMD070 (X4Pꢀ001),10ꢀ11
and GSK 81239712ꢀ13 have been reported in the literature
(Figure 1). The bicyclam AMD3100 was the first generation
CXCR4 antagonist developed by AnorMED but exhibited
poor oral bioavailability and doseꢀlimiting adverse events.
Subsequently, AMD070 improved oral bioavailability and
eliminated the adverse interactions associated with cyclams.
However, this structure suffered from cytochrome P450 2D6
inhibition,14 likely due to the 2ꢀsubstituted benzimidazole.15
The 2D6 isoform is primarily expressed in the liver and is
responsible for the metabolism of nearly 25 percent of all
drugs.16 Strong inhibition of 2D6 leads to drugꢀdrug interacꢀ
tions and detracts from future therapeutic value. Exchanging
the benzimidazole moiety with other heterocycles was exꢀ
pected to reduce such offꢀtarget effects.
Previous Work:
This Work:
X
R
R
N
N
R1
TIQ-15
N
N
R1-R3 = H
N
N
NH HN
R1
N
N
N
N
HN
HN
NH
N
2°
N
N
N
R2
N
Me
N
NH2
NH2
1°
R3
OH
HN
N
Open System
NH2
Fused System
R1, R2, R3 = H, Alkyl,
NMe
N
HN
Amido, Benzyl, Heteroaryl
X = CH2, O
Currently in Phase II/III
NH
HN
for WHIM
Figure 2. Derivatization of TIQ-15 and New Approach to Tet-
rahydroquinoline Replacement.
AMD070/X4P-001
X4 Pharma
GSK 812397
GlaxoSmithKline
AMD3100
(Plerixafor
Genzyme / Sanofi
)
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ACS Medicinal Chemistry Letters
Recently, our group disclosed the discovery of TIQꢀ15, a poꢀ
Page 2 of 7
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tent small molecule 1,2,3,4ꢀtetrahydroisoquinoline (THIQ)
based CXCR4 antagonist (Figure 2).17 Subsequent synthetic
efforts focused on increasing lipophilicity by attenuating the
basicity of the 1° and 2° amine moieties of TIQꢀ15. Various
analogs bearing alkyl, amido, benzyl, and heteroaryl substituꢀ
tions on the 2° nitrogen or the 1° butyl amine of TIQꢀ15 were
synthesized; nevertheless, the parent compound remained the
most attractive analog. A critical aspect of this investigation
was to improve upon TIQꢀ15 as an orally administrable comꢀ
pound. To address this, we conducted biotransformation studꢀ
ies of TIQꢀ15 in human liver microsomes (HLM). Interestingꢀ
ly, these studies revealed no metabolites over 120 minutes
when monitored by LCꢀMS. Upon incubation with mouse
liver microsomes (MLM) rapid metabolism of the tetrahydroꢀ
quinoline (THQ) ring was observed. In order for an accurate
evaluation of our compounds in a mouse model, it was essenꢀ
tial to determine the first pass metabolites in MLM for TIQꢀ15
and tune out that metabolic liability. The biotransformation
study with MLM exposed oxidation metabolites of the THQ
moiety (M1 and M2, Chart 1) monitored by LCꢀMS.
Scheme 1. Synthesis of Pyran Analog 8
9
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Reagents: a) Ti(OiPr)4, NaBH(OAc)3, THF, 35%; b) TFA,
DCM 85%, 39%; c) BH3·Me2S, THF, 90%; d) (COCl)2, DMSO,
Et3N, CH2Cl2, 63%; e) NaBH(OAc)3, 1,2ꢀDCE, 3, 77%; f)
NaBH(OAc)3, 1,2ꢀDCE, 6, 51%; g) TFA, DCM , 39%.
Chart 1. Metabolism of TIQ-15 in MLM
O
Chart 2. Metabolism of Pyran 8 in MLM and HLM
N
N
H2N
N
M3 +14 (RT: 4.09)
ꢀ2H + O
H
M1 +16
M2 +16
O
O
Top Fast Forming AUC's in MLM
N
N
TIQ-15
M1+16
M2+16
N
100
80
60
40
20
0
HN
H2N
N
N
H
H
M5ꢀ57 (RT: 4.77)
ꢀ2H + O
M4 +14 (RT: 4.00)
ꢀ2H + O
10
5
Top Fast Forming AUC's (MLM)
Pyran 8
M4+14
M5-57
50
40
30
20
10
0
100
50
0
0
0
5
10
15
Time (min)
We sought to inhibit MLM metabolism of the THQ by incorꢀ
porating an oxygen into the ring. Our goal was to improve
upon the metabolic stability in both human and mouse liver
microsomes while maintaining CXCR4 antagonist potency.
Commercially available ketone 1 was transformed to pyran 8
in five synthetic steps (Scheme 1). Reductive amination of
ketone 1 and (R)ꢀ1ꢀ(4ꢀmethoxyphenyl)ethanꢀ1ꢀamine 2 folꢀ
lowed by trifluoroacetic acid (TFA) mediated removal of the
paraꢀmethoxybenzyl (PMB) moiety delivered chiral amine
3.18ꢀ19 Aldehyde 5 was produced from commercially available
carboxylic acid 4 via borane reduction to the alcohol and
Swern conditions20 for oxidation. Amine 3 and aldehyde 5
were treated with sodium triacetoxyborohydride in 1,2ꢀ
dichloroethane to yield secondary amine 6. A final reductive
amination of butyraldehyde 7 and amine 6 with subsequent
removal of the carbamate protecting groups revealed pyran
analog 8.
0
5
10
15
Time (min)
Top Fast Forming AUC's (HLM)
Pyran 8
M3+14
M5-57
100
80
60
40
20
0
8
6
4
2
0
0
5
10
15
Time (min)
We discovered that our strategy to block metabolism in MLM
with pyran 8 shifted the metabolic liability to the THIQ moiety
(Chart 2a, MLM). However, comparing TIQ-15 with pyran 8,
more parent compound remained at 15 min in Chart 2a vs.
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Chart 1. Metabolism of pyran 8 with MLM generated a soft
calcium flux assays were more appropriate for initial measꢀ
urements of onꢀtarget activity. Second, allosteric binders can
evade detection by competition ligand binding assays that
employ labelled orthosteric binders, commonly leading to
false negatives. The compounds described herein block the
functional response of SDFꢀ1/CXCR4 ligand/receptor interacꢀ
tions as either orthosteric or allosteric antagonists.
1
2
3
4
5
6
7
8
spot that was subjected to oxidation and dehydrogenation as
identified by LCꢀMS fragmentation (M4). Incubation of pyran
8 in HLM revealed two distinct metabolites: M3 and M5. M3
formed due to oxidation and dehydrogenation of the THIQ
ring. The formation of M5 was due to an oxidation and dehyꢀ
drogenation of the THIQ, in combination with a dealkylation
of the tertiary amine (M5, green circle). The observed metaboꢀ
lism of pyran 8 in MLM and additional HLM metabolites warꢀ
ranted a more extensive SAR to improve microsomal stability.
Scheme 3. Synthesis of Three (S, R) Analogs
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Scheme 2. Synthesis of 3-Methyl THQ Compound 13
a-c
d-f
N
N
N
N
Reagents: a) NaBH(OAc)3, CH2Cl2, 2 (27ꢀ45%); b) TFA (49ꢀ
98%); c) NaBH(OAc)3, 5, 1,2ꢀDCE (67ꢀ80%); d) NaBH(OAc)3,
7, 1,2ꢀDCE; e) TFA, CH2Cl2 (36ꢀ61% over 2 steps).
OH
NH2
9
10
11
g
h,i
Analogs with benzylic methyl substitution maintaining the
same chiral configuration as TIQꢀ15 (S, R) were analyzed first
(Scheme 3). These compounds were prepared using the proceꢀ
dure adapted from Boggs et al.12 Reductive aminations with 2
and 2ꢀacetyl pyridines 14a-c provided a mixture of diastereꢀ
omers with an approximate ratio of 4:1 favoring the desired
(S,S) conformation. The (S,S) diastereomer was separated via
column chromatography followed by recrystallization in hexꢀ
anes to provide Xꢀray quality crystals, which were used to
assign the absolute stereochemistry (see Supporting Inforꢀ
mation). TFA mediated removal of the PMB moiety revealed
chiral amino pyridines with the desired (S) configuration 15a-
c. The chiral amines 15a-c were reacted as described previousꢀ
ly in successive reductive aminations with aldehyde 5, then 7,
followed by carbamate deprotection protocol to furnish comꢀ
pounds 16a-c.
N
N
H2N
N
H
HN
N
13
12
Boc
Reagents: a) AcOH, H2O2; b) Ac2O; c) K2CO3, MeOH, 35%
over 3 steps; d) (COCl)2, DMSO, Et3N, CH2Cl2, 75%; e)
NaBH(OAc)3, 2, 1,2ꢀDCE, 61%; f) TFA, 93% g) NaBH(OAc)3, 5,
1,2ꢀDCE, 70%; h) NaBH(OAc)3, 7, 1,2ꢀDCE, ; i) TFA, CH2Cl2,
74% over 2 steps.
Incorporation of substituents onto the THQ required long synꢀ
thetic sequences and limited our ability to conduct efficient
SAR studies. For instance, in order to produce a methyl substiꢀ
tution at the 3ꢀposition we used the following strategy
(Scheme 2). Nꢀoxidation of 3ꢀmethyl tetrahydroquinoline 9
followed by a Boekelheide rearrangement21 and hydrolysis of
the acetyl ester provided alcohol 10. Swern oxidation followed
by the Boggs12 protocol delivered chiral amine 11. Two conꢀ
secutive reductive aminations, first with aldehyde 5 and then
butyl aldehyde 7, delivered the carbamate intermediate that
was treated with TFA to afford the desired compound 13. The
final compound 13 was synthesized in nine total steps only to
discover that although CXCR4 potency was retained, mouse
liver microsomal stability was significantly worse than TIQꢀ15
and pyran 8 (Table 1, entries 1ꢀ3).
Table 1. SAR for Benzylic Methyl (S, R) Analogs
Given the lengthy synthesis required to incorporate substituꢀ
tions onto the conformationally restricted THQ moiety (8 and
13), we chose to access new molecules more rapidly by openꢀ
ing the THQ into substituted 2ꢀ(aminomethyl)pyridines, quinꢀ
olines and isoquinolines, which were more readily available.
Similar studies with pyridine analogs have been conducted
using AMD070 as the parent structure and we anticipated the
CXCR4 activity of this new series of compounds to follow a
similar trend.22 However, there have been no reports on microꢀ
somal stability for these molecules. The properties that we
sought to improve upon were 1) inhibition of SDFꢀ1 induced
Ca2+ flux and 2) liver microsomal stability while avoiding off
target interactions, such as mAChR23 inhibition. Intracellular
calcium release is a basic functional assay that measures
GPCR activity and inhibition thereof. Calcium flux assays
were chosen over ligand binding assays as the primary onꢀ
target screen for several reasons. First, calcium flux assays are
functional assays that give information regarding receptor
activation, potentiation, inhibition, etc., as opposed to compeꢀ
tition ligand binding assays, which convey no functional inꢀ
formation. Since inhibition of CXCR4 signaling was desired,
Entry
R
CXCR4
mAChR Ca2+
Flux
LM %a
R
Ca2+ Flux
(IC50) nM
(IC50) nM
>30000
>16700
>16700
28500
H
M
1
2
3
4
5
6
a
TIQ-15
8
13
H (16a)
3ꢀMe(16b)
5ꢀMe(16c)
7
6
11
62
1710
24
77
91
84
97
37 17
3
7
39
2
77 79
33000
6100
100 22 11
79
1
5
Liver microsomal stability measured as percent remaining by
LCꢀMS after ten minutes in Human (H), Rat (R) and Mouse (M).
The assay results from compounds 16a-c (Table 1, entries 4ꢀ6)
provided unexpected data. The potency (IC50) for these comꢀ
pounds was defined as the concentration of the compound
required to inhibit 50% of the SDFꢀ1 induced Ca2+ signaling.
Unsubstituted pyridine 16a revealed a 10ꢀfold decrease in
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CXCR4 potency in comparison to TIQ-15, while significantly with a slight drop in CXCR4 antagonist activity, exemplified
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increasing microsomal stability (Table 1, entry 4). The 3ꢀ
methyl pyridine 16b exhibited nearly a 100ꢀfold loss in
CXCR4 potency and a substantial reduction in RLM and
MLM stability. The loss in CXCR4 potency could be due to
steric clash between the benzylic methyl and the 3ꢀmethyl
substituent, which might hinder the molecule from attaining
the appropriate conformation for receptor binding. Conversely,
the 5ꢀmethyl pyridine 16c showed a 3ꢀfold improvement in
potency compared to 16a, but liver microsomal stability sufꢀ
fered. Initially, the pyridine moiety 16a validated that an open
framework could improve metabolic stability and maintain
decent potency; however, introducing additional methyl
groups onto this framework (16b and 16c) proved to be deleteꢀ
rious to RLM and MLM stability. Compound 13 corroborates
this result by showing a marked decrease in mouse liver miꢀ
crosomal stability compared to pyran 8. Continuing with our
analysis of pyridine substituents, we chose to remove the (S)
chiral center and utilized substituted pyridineꢀ2ꢀ
carboxaldehyde moieties as starting materials. These building
by 20h.
When comparing the unsubstituted pyridine analog 20a with
the unsubstituted quinoline analogs 20b-20d, the pyridine was
determined to be the superior antagonist. Establishing the pyrꢀ
idine as higher priority, we began by substituting a methyl
group at each position of the pyridine 20e-20h . We observed
that the 5ꢀmethyl (20f, 71 nM) and 3ꢀmethyl (20h, 21 nM)
substituents demonstrated the greatest potency and improved
MLM stability. At this point, our focus was to test different
functional groups (electron donating and electron withdrawꢀ
ing) at the 3ꢀ and 5ꢀpositions to evaluate the effect on CXCR4
potency. Halogen (Cl, F) substitution was best suited at the 5ꢀ
position (20i, 20l), whereas 3ꢀ or 5ꢀmethoxy (20n, 20o) and 5ꢀ
trifluoromethyl 20p substituted analogs were inactive. Interꢀ
estingly, a 3ꢀtrifluoromethyl 20q substituent retained moderate
activity as well as a 3ꢀvinyl 20s and 3ꢀcyclopropyl 20r, which
was an alkyl modifier in an attempt to improve upon the propꢀ
erties associated with the 3ꢀmethyl substituted compound 20h.
The 3,5ꢀdimethyl analog 20t was equipotent to 20f but elicited
weaker inhibition of muscarinic acetylcholine receptor comꢀ
pared to 20h. Compound 20t also had an enhanced stability in
HLM and MLM. It was posited that a synergistic effect would
be observed between analogs 20h and 20l if the 5ꢀmethyl
group was exchanged with a fluorine 20u. We observed a 5ꢀ
fold reduction in CXCR4 activity for 20u, compared to 20h,
but we benefitted from a loss in muscarinic activity and inꢀ
creased microsomal stability. Substituted thiazoles were also
tested, but compounds containing these moieties were inactive
in the CXCR4 Ca2+ flux assay (see Supporting Information).
9
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blocks
provided
access
to
monoꢀsubstituted
2ꢀ
(aminomethyl)pyridines, eliminating two synthetic steps and
providing a more rapid production and analysis pipeline.
Scheme 4. Synthetic Sequence to Access Open Scaffold
Table 2. Open Scaffold SAR
Reagents: a) NaBH(OAc)3, H2N(CH2)4NHBoc (18), 1,2ꢀDCE
(29ꢀ83%); b) 5, NaBH(OAc)3, 1,2ꢀDCE; c) TFA, CH2Cl2 (56ꢀ86%
over 2 steps); d) NiCl2·6H2O, NaBH4, Boc2O, MeOH, 0°C to rt; e)
TFA, CH2Cl2 (55ꢀ78% over 2 steps); f) 5, NaBH(OAc)3, 1,2ꢀDCE
(57ꢀ82%); g) NaBH(OAc)3, 7, 1,2ꢀDCE; h) TFA, CH2Cl2 (31ꢀ
58% over 2 steps).
Compound
R
CXCR4
mAChR Ca2+
Flux
LM %b
R
Ca2+ Flux
(IC50) nMa
(IC50) nM
11500
>16700
4350
>16700
10700
23200
H
M
20a
20b
H
2ꢀquin
230
100 33 77
5751
8721
3307
2902
71
698
21
631
>33000
1855
260
2116
>23000
>33000
>33000
406
163
484
69
127
88
88
8
5
35
62
20c
20d
20e
20f
1ꢀisoquin
3ꢀisoquin
6ꢀMe
In our open scaffold series, compounds 19a-s could be obꢀ
tained after a simple reductive amination with commercially
available pyridine carboxaldehydes 17a-s and butyl amine 18
using STABꢀH in 1,2ꢀdichloroethane (Scheme 4). A subseꢀ
quent reductive amination with the secondary amines 19a-s
and aldehyde 5 followed by carbamate removal furnished final
compounds 20a-s. The 3,5ꢀdiꢀsubstituted pyridine series 20t-v
were obtained via the 2ꢀcyanoꢀpyridine derivatives 21t-v. The
cyano group was reduced using nickel boride prepared in situ
in the presence of diꢀtertꢀbutyl dicarbonate to yield the Bocꢀ
protected primary amines.24 TFA mediated deprotection folꢀ
lowed by consecutive reductive aminations with 5, then 7 and
a final deprotection provided the finished compounds 20t-v.
100 31 45
100 34 ND
5ꢀMe
4ꢀMe
3ꢀMe
5ꢀCl
4ꢀCl
3ꢀCl
5ꢀF
3ꢀF
100
87
86
89
89
3
67
20g
20h
20i
20j
20k
20l
3000
5900
30 74
33 64
5
>16700
>33000
>16700
>33000
>16700
>27000
>33000
>21000
>33000
>16700
>16700
>33000
>33000
11,630
56
31 ND
100 14 43
88
83
92
10 76
64
13 69
20m
20n
20o
20p
20q
20r
20s
20t
9
5ꢀOMe
3ꢀOMe
5ꢀCF3
3ꢀCF3
3ꢀcPr
3ꢀvinyl
3,5ꢀdiMe
3ꢀMeꢀ5ꢀF
5ꢀMeꢀ3ꢀF
100 38 99
98 85
100 66 82
8
Overall, twenty two molecules with various functional group
substitutions on the pyridine moiety were synthesized and
screened for 1) improved potency in a CXCR4 Ca2+ flux assay,
2) limited offꢀtarget interaction with mAChR receptor and 3)
increased liver microsomal stability (Table 2). In comparison
to the constrained moieties (Table 1, entries 1ꢀ3), the open
scaffold markedly improved upon metabolic stability albeit
90
86
29 56
44
4
100 39 79
100 36 91
20u
20v
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86
18 51
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aSee Supporting Information for standard deviation. b Liver miꢀ
crosomal stability measured as percent remaining by LCꢀMS after
ten minutes in Human (H), Rat (R) and Mouse (M). ND = not
determined.
liver microsomes; MLM, mouse liver microsomes; PMB, paraꢀ
methoxybenzyl; TFA, trifluoroacetic acid; DCE, 1,2ꢀ
dichloroethane; mAChR, muscarinic acetylcholine receptor;
STABꢀH, sodium triacetoxyborohydride; PAMPA, parallel artifiꢀ
cial membrane permeability assay;
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9
Additional parameters including parallel artificial membrane
permeability assay (PAMPA) and cytochrome P450 (CYP450)
inhibition were analyzed. Unfortunately, we observed little to
no passive membrane permeability. In the CYP450 assays,
inhibition resulting from this chemotype was solely observed
on isoform 2D6 (see Supporting Information). Overall, the
open methylꢀsubstituted pyridine analogs showed a modest
decrease in CXCR4 activity; however, they showed promise
due to the increased microsomal stability compared to TIQꢀ15.
This suggests that a more robust compound could be derived
from an open pyridine analog.
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In summary, we have developed a series of CXCR4 antagoꢀ
nists that possess increased liver microsomal stability in huꢀ
man and mouse models compared to the parent molecule TIQꢀ
15. Specifically, compounds 20c, 20e and 20t bearing methyl
substituents around a pyridylmethyl moiety seem to be the
most promising. Ultimately, we have significantly progressed
this scaffold and intend to continue to improve upon the memꢀ
brane permeability (PAMPA, Cacoꢀ2) and reduce CYP450
activity of this series. This and other studies will be presented
in due course.
ASSOCIATED CONTENT
Supporting Information
Experimental and characterization data for all new compounds
and all biological data. The Supporting Information is available
free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: dliotta@emory.edu, ljwilso@emory.edu
Author Contributions
The manuscript was written by RJW and through contributions of
all authors. All authors have given approval to the final version of
the manuscript.
Funding Sources
The authors acknowledge the use of shared instrumentation proꢀ
vided by grants from NSF (CHE1531620).
Notes
DCL is the principle investigator on a research grant from Bristolꢀ
Myers Squibb Research and Development to Emory Universiꢀ
ty. DCL, LJW, EJM, EJ, HHN, YAT, RJW, VMT, and MBK are
coꢀinventors on Emoryꢀowned Intellectual Property that includes
CXCR4 antagonists.
14. Nyunt, M. M.; Becker, S.; MacFarland, R. T.; Chee, P.;
Scarborough, R.; Everts, S.; Calandra, G. B.; Hendrix, C. W.,
Pharmacokinetic effect of AMD070, an Oral CXCR4 antagonist, on
CYP3A4
and
CYP2D6
substrates
midazolam
and
ACKNOWLEDGMENT
dextromethorphan in healthy volunteers. J. Acquir. Immune
Defic. Syndr. 2008, 47 (5), 559-65.
The authors would like to acknowledge Dr. Shaoxiang Wu of
Emory NMR facility, Dr. John Bacsa for determination of crystal
structure and Dr. Fred Strobel for mass spectrometry.
15. Cao, Y. J.; Flexner, C. W.; Dunaway, S.; Park, J. G.; Klingman,
K.; Wiggins, I.; Conley, J.; Radebaugh, C.; Kashuba, A. D.;
MacFarland, R.; Becker, S.; Hendrix, C. W., Effect of low-dose
ritonavir on the pharmacokinetics of the CXCR4 antagonist
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ABBREVIATIONS
CXCR4, CXC chemokine receptor type 4; GPCR, G proteinꢀ
coupled receptor; CXCL12, CXC chemokine ligand type 12;
THQ,
5,6,7,8ꢀtetrahydroquinoline;
THIQ,
1,2,3,4ꢀ
tetrahydroisoquinoline; HLM, human liver microsomes; RLM, rat
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16. Teh, L. K.; Bertilsson, L., Pharmacogenomics of CYP2D6:
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Kaller, A.; Veale, D.; Yee, H.; Skupinska, K.; Wauthy, R.; Wang, L.;
Baird, I.; Zhu, Y.; Burrage, K.; Yang, W.; Sartori, M.; Huskens, D.;
Clercq, E. D.; Schols, D., Design of novel CXCR4 antagonists that
are potent inhibitors of T-tropic (X4) HIV-1 replication. Bioorg.
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that
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Synthesis and SAR of 1,2,3,4-Tetrahydroisoquinoline Based
CXCR4 Antagonists
Robert J. Wilson;§ Edgars Jecs;§ Eric J. Miller;§ Huy H. Nguyen;§ Yesim A. Tahirovic;§ Valarie M. Truax;§ Michelle
B. Kim;§ Katie M. Kuo;§ Tao Wang;‡ Chi Shing Sum;‡ Mary E. Cvijic;‡ Anthony A. Paiva; ‡ Gretchen M.
Schroeder;‡ Lawrence J. Wilson;§* Dennis C. Liotta§ *
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§Department of Chemistry, Emory University, 1515 Dickey Drive NE, Atlanta, GA 30322, United States
‡Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States
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