Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.06.145

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Full text of DOI:10.1016/j.bmcl.2010.06.145

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5269–5273
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally
bioavailable LFA-1/ICAM-1 antagonists
*
Min Zhong , Wang Shen, Kenneth J. Barr, Jennifer P. Arbitrario, Michelle R. Arkin, Minna Bui, Teresa Chen,
Brian C. Cunningham, Marc J. Evanchik, Emily J. Hanan, Ute Hoch, Karen Huen, Jennifer Hyde,
Jeffery L. Kumer, Teresa Lac, Chris E. Lawrence, Jose R. Martell, Johan D. Oslob, Kumar Paulvannan,
Saileta Prabhu, Jeffrey A. Silverman, Jasmin Wright, Chul H. Yu, Jiang Zhu, W. Mike Flanagan
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., Suite 400, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small mol-
ecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation
through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent
in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good
oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration
of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced
murine peritonitis model.
Received 5 March 2010
Revised 25 June 2010
Accepted 29 June 2010
Available online 23 July 2010
Keywords:
Leukocyte function-associated antigen-1
(LFA-1)
Ó 2010 Elsevier Ltd. All rights reserved.
Intercellular adhesion molecule-1 (ICAM-1)
Tetrahydroisoquinoline (THIQ) derivative
Antagonist
Integrin-mediated, cell–cell adhesive interactions between leu-
kocytes and endothelialcells effect both T-cell trafficking, migration,
priming, and activation, and as such are believed to be critical to the
initiation and maintenance of immune responses.1–3 A heterodimer-
ic member of the b2 family of integrins, leukocyte function-associ-
discovery of small molecule-based LFA-1 antagonists13–21 has been
the subject of an extensive commitment by the pharmaceutical
industry.
A variety of potent small molecules (Fig. 1) have been reported to
bind to either direct16d or allosteric (IDAS)13–15 competitive binding
sites within LFA-1’s inserted I-domain. For example, 1H NMR or a
combination of immunochemical and molecular modeling studies
showed hydantoin derivatives, such as 113a and 2,14b and diphenyl
sulfideanalog, suchas3,15a bindattheIDAS. In contrast,a fluorescein
labeling study demonstrated that N-benzoyl amino derivative 4 di-
rectly inhibits the interaction of LFA-1 and ICAM-1 by binding to a
high-affinity site on LFA-1. This binding site overlaps with the
ated antigen-1 (LFA-1,
aLb2, CD11a/CD18) plays a key role in
inflammation and other T-cell specific immune responses through
mediating cell adhesion, leukocyte extravasation and migration,
antigen presentation, and augmentation of T-cell receptor signal-
ing.4 The interaction between LFA-1 and intercellular adhesion
molecule-1 (ICAM-1, CD54) is implicated in numerous immunoreg-
ulatory diseases, such as graft rejection, arthritis, and psoriasis. In
vivo studies using anti-LFA-1 antibodies or LFA-1-deficient mice
suggest that inhibition of the binding of LFA-1 to ICAM-1 has the po-
tential for treating these diseases.5–10 In 2003, humanized monoclo-
nal anti-LFA-1 antibody efalizumab (RaptivaÒ) was approved for the
treatment of psoriasis, and was reported to be effective in the
treatment of transplant rejection.11 Thus, the efficacy of efalizumab
provides an important proof-of-principle for LFA-1 as a viable ther-
apeutic target. However, efalizumab had to be administered by sub-
cutaneous injection and was expensive to produce. Also, long term
use of efalizumab has caused undesirable side effects.12 Therefore,
ICAM-1 binding site on the a-subunit of LFA-1, which has previously
been localized to the I-domain.16d Many of these small molecules
have excellent in vitro and in vivo properties. Moreover, an antago-
nist (IC747)22 related to 3 was advanced as far as Phase IIb human
clinical trials in patients with moderate to severe psoriasis. Herein,
we present the discovery of a novel series of tetrahydroisoquinoline
(THIQ)-derived antagonists that potently inhibit the adhesion of hu-
man lymphoma T-cells (Hut-78 cells) to immobilized ICAM-1. This
inhibition results from disruption of the binding of LFA-1 to ICAM-
1, since LFA-1 is the dominant ICAM-1 binding integrin expressed
on the surface of Hut-78 cells.1
In comparison to those reported I-domain allosteric com-
pounds, direct competitive antagonists seemed to have consider-
ably better in vitro potency as suggested by those N-benzoyl
* Corresponding author. Current address: Presidio Pharmaceuticals, Inc., 1700
Owens Street, Suite 585, San Francisco, CA 94158, USA. Tel.: +1 415 655 7567.
E-mail address: mzhong@presidiopharma.com (M. Zhong).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.145

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M. Zhong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5269–5273
a preferred conformation of ‘right-wing’; and various linkages can
be tolerated to connect the ‘left-wing’ to the central functionalized
phenyl moiety without affecting the potency of binding affin-
ity.16a,24 Hence, we designed a novel series of LFA-1 antagonists
using a bicyclic tetrahydroisoquinoline (THIQ) central scaffold to
link both ‘left-wing’ and ‘right-wing’. As shown in Figure 2, as-
sumed the amide bond of 5 was not critical to the binding affinity,
its –NH could be cyclized with the phenyl residue at C3 position to
give a novel series of THIQ-derived LFA-1 antagonists (6)25 (Fig. 2).
Preparations of the THIQ scaffold and its derivatives as LFA-1
antagonists were carried out as shown in Scheme 1. Commercially
available 7 was refluxed with aqueous formaldehyde (37 wt %) un-
der an acidic condition,26 followed by treatment with 48% aqueous
HBr27 and subsequent N-Boc protection, to give 8 in quantitative
yield. Reaction of 8 and surfuryl chloride in acetic acid and N-Boc
protection afforded 9 in 85% yield. Subsequently, 9 was converted
to its corresponding triflate, which underwent a palladium-cata-
lyzed carbonylation to generate 10 in 56% yield. Finally, 6a–t bear-
ing various R1 and R2 moieties were readily assembled via either 11
or 12 by employing different sequences of Boc-deprotection, amide
formation, and saponification.
Compounds 6a–t were first evaluated in a cellular adhesion assay
by measuring inhibition of the binding of Hut-78 cells to immobi-
lized ICAM-1.25 Compounds demonstrating good potency (IC50
6100 nM) were subsequently evaluated in a Staphylococcal Entero-
toxin B (SEB)-stimulated T-cell activation assay in the presence of
10% fetal bovine serum (FBS).28 Reduced activities in SEB assay rela-
tive to Hut-78 assay were anticipated partly due to potential serum
protein bindings.29 Compounds showing potent antagonism of LFA-
1/ICAM-1 interaction in Hut-78 assay (630 nM) and good inhibition
of T-cell activation in SEB assay (6500 nM) were advanced into
pharmacokinetic (PK) profiling in rat.
Figure 1. Representative LFA-1/ICAM-1 antagonists.
amino acid-derived analogs.16a Moreover, the binding site of these
direct competitive LFA-1 antagonists was a newly identified one
and no compounds that bind to this site had been advanced to clin-
ical trials when we initiated this project.23 Therefore, the direct
competitive binding site represented an attractive binding site to
allow us develop novel LFA-1 antagonists.
As expected, 6a shows good potency in Hut-78 assay (Table 1,
entry 1). Although 6a is less potent than the corresponding refer-
ence compound 5 (IC50 = 0.005 lM in Hut-78 assay), it demon-
strates THIQ is a viable scaffold. Encouraged by this positive
result, we initiated SAR study to understand the impact of R1 and
R2 on the potency.
Interestingly, the (E)-(2-furyl)vinyl residue of 6a can be readily
replaced with an un-substituted phenyl moiety (6b) (entry 2)
without affecting the activity in Hut-78 assay. Also, 6b shows rea-
sonably good potency in SEB assay. Next, SAR on the phenyl resi-
due was performed. In general, ortho-substitution on the phenyl
In addition to 4,16a Burdick et al.24 disclosed a number of new
scaffolds, including 5 (Fig. 2), using an amide bond instead of an al-
kyl chain to connect the ‘left-wing’ and the central 4-substituted-
2,6-dichlorobenzoic acid moiety. As suggested by the superim-
posed structure of 4 on the crystal structure of the first domain
of ICAM-113a,16a and SAR of derivatives related to 4 and 5, the
‘left-wing’ and ‘right-wing’ are two key binding fragments to the
protein; the central 2,6-dichlorobenzoyl moiety is critical to define
Scheme 1. Reagents and conditions: (a) 37 wt % aq formaldehyde, 1.0 N aq HCl,
reflux; (b) HBr (48%), reflux, 16 h; (c) Boc2O, 2 M aq Na2CO3, THF, rt, 5 h; (d) SO2Cl2
(3 equiv), AcOH/DCM, 0 °C to rt, 16 h; (e) Tf2O, py/DCM, 0 °C to rt, 4 h; (f) Pd(OAc)2
(0.1 equiv), dppp (0.1 equiv), CO (1 atm), TEA, DMF/MeOH, 65–70 °C, 14 h; (g) LiI
(10 equiv), py, 100 °C; (h) amino acid methyl ester, HATU, DIEA, DMF, rt, 16 h; (i)
TFA, DCM, rt; (j) R2COOH, HATU, DIEA, DMF, 45 °C; (k) LiOH, THF/H2O, rt.
Figure 2. Evolution of novel THIQ-derived LFA-1/ICAM-1 antagonists.

M. Zhong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5269–5273
5271
Table 1
In vitro and in vivo properties of 6a–t
a
Entry
Compd
R1
R2
R3
Hut-78 IC50
(l
M)
SEB-10% FBSb IC50
(l
M)
Rat iv PKc
t1/2 (h)
CL (mL/min/kg)
AUC (h à ng/mL)
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
6a
6b
6c
6d
6e
6f
6g
6h
6i
(E)-(2-Furyl)vinyl
Phenyl
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
0.025
0.079
0.46
0.090
0.010
0.066
0.022
>1.0
0.62
0.54
0.029
0.051
>1.0
0.81
>1.0
>1.0
0.009
0.013
0.005
—
—
—
—
—
—
—
—
—
—
—
—
—
—
1.2
—
2-Methylphenyl
3-Methylphenyl
4-Methylphenyl
3-Chlorophenyl
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
4-Chlorophenyl-
Methyl
—
1.6
0.24
0.43
—
—
—
—
1.1
1.4
—
—
—
0.7
—
—
—
—
>60
31
—
—
—
>60
—
—
—
—
120
580
—
—
—
487
—
—
—
—
–NHAc
–NHCOc-Hex
–NHCOPhenyl
—
—
6j
6k
6l
0.55
3.8
—
–NHCO(2-furyl)
-3-Hydroxyphenyl
-3-Indolyl
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
–NHCO(2-thienyl)
6m
6n
6o
6p
6q
6r
6s
6t
—
—
—
c-Hex
6-Benzofuryl
[2,3]-2H-6-Benzofuryl
2-Benzofuryl
6-Benzofuryl
—
—
—
0.26
0.65
0.069
—
3.0
1.1
1.5
2.8e
3.2
19
>60
5.0e
5495
4867
1260
16,850e
a
b
c
The IC50 value is an average of three titrations with eight concentration points.
Fetal bovine serum.
PK experiments were carried out with a single dose of 5 mg/kg of a testing compound using a group of three male Sprague–Dawley rats.
Not determined.
d
e
The compound was administered in ester form, which was rapidly hydrolyzed in vivo to parent acid 6q, so the data presented are for measured 6q.
residue has a negative effect on the potency (entry 3) while both
meta- and para-substitutions can be tolerated (entries 4–7). Rat
intravenous (iv) PK profiling indicates that the p-Cl substituted
analog (6g) (entry 7) has better PK properties than the correspond-
free carboxylic acid moiety.30 Therefore, a prodrug strategy was
then applied to improve the oral bioavailability of 6q. Compound
6q was subsequently converted to its ethyl ester (6t), which
showed significant improvement of cell permeability relative to
6q, determined by MDCK assay (Papp 8.5 Â 10À6 cm/s (A/B) and
10 Â 10À6 cm/s (B/A) for 6t; and Papp 0.34 Â 10À6 cm/s (A/B) and
0.3 Â 10À6 cm/s (B/A) for 6q). After iv administration of 6t in rat,
only parent acid 6q was detected in the blood samples from the
PK study. Interestingly, even though the ethyl ester was rapidly
hydrolyzed in vivo, significantly enhanced rat iv PK profile was ob-
served for 6t when compared to 6q (entry 20 vs entry 17, Table 1),
with a much higher area under the curve (AUC) while maintaining
similar half life (t1/2) and clearance (CL). Possibly, the ethyl ester
prodrug (6t) has wider distribution in rat than the free carboxylic
acid (6q) after iv administration.
More importantly, 6t is orally bioavailable in both mouse
(F = 27% at 20 mg/kg and F = 31% at 100 mg/kg) and rat (F = 18%
at 20 mg/kg), and demonstrates dose-linear PK profiles in mouse
(Table 2).
Finally, the in vivo efficacy of 6q and 6t was evaluated with a
thioglycollate-induced murine peritonitis model.31 Compound 6q
was intravenously administrated in one experiment, while its ethyl
ing m-Cl substituted analog (6f) (entry 6). For these L-2,3-diamino-
propionic acid (DAP) derived analogs, the free b-amine residue is
preferred to be capped as an aromatic amide instead of an aliphatic
amide (entries 8–12). Predictably, the thienyl residue of 6g could
be replaced with a phenyl group (6k) to maintain the potency (en-
try 11); however, 6k showed an inferior rat iv PK profile to that of
6g. Additionally, replacement of the thienyl moiety of 6g with a
furyl residue was tolerated in Hut-78 assay, but there was a signif-
icant decrease of the potency in SEB assay. It is worth mentioning
that initial attempts to replace DAP with other amino acids with
less peptide characteristics were not fruitful (entries 13–14).
With 6g in hand, our efforts were then directed to further study
the SAR of ‘left-wing’ residue R1. In general, aliphatic residues
showed reduced potency relative to aromatic ones (entries 15–16).
When a fused 6-benzofuryl moiety (6q) was used, significant
improvement of the potency in Hut-78 assay was observed (entry
17). Moreover, the corresponding saturated dihydrobenzofuran
derivative (6r) demonstrated comparable potency in both Hut-78
and SEB assays (entry 18); however, its rat iv PK profile was inferior
to that of 6q. Although substantial improvement of the potency in
SEB assay was achieved by replacing the 6-benzofuryl residue of
6q with a 2-benzofuryl moiety (6s), the rat iv PK profile of 6s was
unfavorable (entry 19).
Table 2
Oral PK profiles of 6t in rat and mousea,b
Species Dose (mg/kg) Tmax (h) Cmax (ng/mL) AUClast (h à ng/mL) F (%)
Rat
Mouse
Mouse 100
20
20
0.8
0.8
1
3395
2117
8460
13,853
5545
31,895
18
27
31
The SAR on both ‘left-wing’ and ‘right-wing’ of these THIQ-de-
rived LFA-1/ICAM-1 antagonists is similar to those compounds dis-
closed by Burdick et al.16a–c suggesting they have similar binding
mode to LFA-1.
Poor cellular permeability was found with these THIQ-derived
analogs bearing a DAP residue, possibly due to the presence of a
a
PK experiments were carried out using male Sprague–Dawley rats or female
C57BL/6 mice administrated orally with a single given dose of 6t.
b
Compound 6t was rapidly hydrolyzed in vivo to parent acid 6q, so the data
presented are for measured 6q.

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M. Zhong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5269–5273
Chart 1. Efficacy of 6q and its ethyl ester (6t) in a thioglycollate-induced murine peritonitis model. Experiments were carried out using a group of eight female c57Bl/6 mice
administrated iv for 6q and po for its ethyl ester (6t) at different levels 15 min prior to intraperitoneal (ip) injection of thioglycollate. Blood samples were collected 4 h post ip
injection of thioglycollate and neutrophils were counted.
ester prodrug (6t) was orally dosed in parallel. For comparison, a
murine LFA-1 antibody, mAb M 17/4, was dosed at 5 mg/kg as a
positive control. As shown in Chart 1, preliminary data indicated
that both 6q and its ethyl ester prodrug (6t) had dose-dependent
inhibition of neutrophil recruitment with ED50’s of 0.038 mg/kg
and 6.4 mg/kg, respectively.
In summary, we successfully discovered a novel series of tetra-
hydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists.
Compound 6q not only has good in vitro potency and PK parame-
ters, but also possesses encouraging in vivo efficacy in a thioglycol-
late-induced murine peritonitis model. Its ethyl ester prodrug (6t)
demonstrates moderate oral bioavailability in both mouse and rat.
The discovery of 6q and its ethyl ester prodrug (6t) has justified
further studies of this novel series of potent LFA-1/ICAM-1
antagonists.
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