Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye

Article abstract of DOI:10.1021/ml2002482

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

Full text of DOI:10.1021/ml2002482

Letter
pubs.acs.org/acsmedchemlett
Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR
1118 as an Ophthalmic Solution for Treating Dry Eye
Min Zhong,*,†,§ Thomas R. Gadek,*,‡ Minna Bui,† Wang Shen,† John Burnier,‡ Kenneth J. Barr,†
Emily J. Hanan,† Johan D. Oslob,† Chul H. Yu,† Jiang Zhu,† Michelle R. Arkin,† Marc J. Evanchik,†
W. Mike Flanagan,† Ute Hoch,† Jennifer Hyde,† Saileta Prabhu,† Jeffrey A. Silverman,† and Jasmin Wright†
†Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States
‡SARcode Bioscience, Inc., 1000 Marina Boulevard, Suite 250, Brisbane, California 94005, United States
S
* Supporting Information
ABSTRACT: LFA-1/ICAM-1 interaction is essential in
support of inflammatory and specific T-cell regulated immune
responses by mediating cell adhesion, leukocyte extravasation,
migration, antigen presentation, formation of immunological
synapse, and augmentation of T-cell receptor signaling. The
increase of ICAM-1 expression levels in conjunctival epithelial
cells and acinar cells was observed in animal models and
patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an
effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-
derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.
KEYWORDS: LFA-1/ICAM-1 antagonist, tetrahydroisoquinoline derivative, SAR 1118, ophthalmic solution, dry eye
ymphocyte function-associated antigen-1 [LFA-1, αLβ2, or
cluster of differentiation 11a (CD11a)/CD18] is a
could offer a targeted T-cell antagonism with improved patient
tolerability for such a chronic ocular disease.
L
heterodimeric member of the β2 family of integrins. Its
interactions with intercellular adhesion molecule-1 (ICAM-1
or CD54) are not only critical to the adhesion, migration, and
proliferation of T-cells at the inflammation sites1−3 but also
have influence on T-cell specific immune responses through
both adhesive interactions and formations of immunological
synapses in conjunction with T-cell receptors and major
histocompatibility complex (MHC).4−6 In the past, interest in
LFA-1 antagonism of ICAM-1 as an approach to identifying
novel anti-inflammatory therapies has focused on psoriasis,
atopic dermatitis, rheumatoid arthritis, and asthma as targets for
systemic treatments.7,8
Recently, we have described the discovery of a series of
potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-
1 antagonists,15,16 which were shown to bind the I-domain of
the CD11a subunit of LFA-1 and serve as direct competitive
antagonists of LFA-1 binding to ICAM-1.17,18 To our
knowledge, most of the marketed ophthalmic solutions resulted
from the repurposing of the drugs developed for nonocular
indications. They typically have reasonable oral bioavailability
and slow clearance from the systemic circulation.19 Interest-
ingly, Atenolol and Propranolol, two controls that are used to
define both para- and trans-cellular uptake of drugs by oral
administration, show similar systemic bioavailability when
delivered as ophthalmic solutions. Additional studies have
demonstrated that molecules as large as monoclonal antibodies
can deeply penetrate into periocular tissues and reach the
systemic circulation after topical administration as an
ophthalmic solution.20 It seems that there is a low barrier to
the absorption of a drug from tears into periocular tissues and
the systemic circulation. For a drug to be topically delivered as
an ophthalmic solution, we thought it would be more
advantageous to select a compound that possesses strong in
vitro potency against the biological target and good solubility in
tears to provide an osmotic gradient for penetration into
periocular tissues, while having poor oral bioavailability and fast
Dry eye [keratoconjunctivitis sicca (KCS), keratitis sicca, or
xerophthalmia] is an ocular disease caused by either decreased
tear production or increased tear film evaporation in humans
and some animals.9 The etiology of this chronic disease is
multifactorial and complex, but emerging evidence supports the
hypothesis that chronic inflammation is an important factor in
the pathogenesis of dry eye.10,11 Conjunctival biopsies from
patients diagnosed with dry eye have implicated the aberrant
presence of CD-3 positive T-cells as the inflammatory basis of
the disease12 and provided a rationale for the use of nonspecific
immunosuppressant cyclosporine (Restasis) in treating dry
eye.13 Also, the increase of ICAM-1 expression levels in
conjunctival epithelial cells and acinar cells of animal models
and patients diagnosed with dry eye was observed.14 Therefore,
we postulated that a small molecule LFA-1/ICAM-1 antagonist
Received: October 24, 2011
Accepted: January 15, 2012
Published: January 31, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
clearance from the systemic circulation. A compound with such
a pharmacokinetic (PK) profile would most likely have low
systemic exposure to avoid unexpected side effects after topical
application.21 Herein, we report the discovery and the
development of a potent direct competitive LFA-1/ICAM-1
antagonist (SAR 1118) (Figure 1) as an ophthalmic solution
for treating dry eye.
benzofur-6-yl “left-wing” residue (1c, entry 3) was found to be
superior to a 4-chlorophenyl moiety (1b, entry 2) in retaining
the potency in the presence of HS. Therefore, we decided to
incorporate a methylsulfonyl moiety into other “right-wing”
amino acids, which previously showed significant serum shift.
All of the new “right-wing” amino acids were readily prepared
and assembled to the functionalized THIQ scaffold following
the disclosed protocols.15,16
Our immediate attempt was to replace the 3-isopropyl
residue in 1a with a 3-methylsulfonyl moiety. To our delight,
the resulting 1d (entry 4) showed great potency in the assay
with 10% HS. The substitution pattern of the methylsulfonyl
moiety is critical to the potency: meta-substitution is optimal,
while both ortho- and para-substitutions (1e−f, entries 5−6)
result in much diminished potency. As expected, merging a
benzofur-6-yl “left-wing” residue with 1d afforded a compound
(1g, entry 7) with improved potency in the presence of 10%
HS.
Next, a structure−activity relationship (SAR) study around
the 3-methylsulfonylphenyl residue was carried out. The
introduction of a substituent at the C5-position on the phenyl
residue seems to be acceptable (1j and 1l, entries 10 and 12),
but with some loss of potency in the presence of 10% HS.
Substitutions at the C2-, C4-, and C6-positions (1h,i and 1k,
Figure 1. Structure of LFA-1/ICAM-1 antagonist SAR 1118 (1g).
We previously reported that many potent THIQ-derived
LFA-1/ICAM-1 antagonists, as exemplified by 1a (Table 1,
entry 1), significantly lost their potency in the HuT 78 T-cell
adhesion assay in the presence of 10% human serum (HS).15,16
To address this serum shift issue, 1b (entry 2) bearing a 2-
methylsulfonylfur-5-yl moiety, was identified. Additionally, a
Table 1. SAR of the α-Amino Acid Residue of the THIQ-Derived LFA-/ICAM-1 Antagonists (1a−w)
e
% at 30 min
rat iv PK
b
HuT 78
IC50 (μM)
HuT 78 + 10% HS
CL
AUC
(h·ng/kg)
a
c
d
entry compd
R1
R2
IC50 (μM)
HLM RLM
t1/2 (h)
(mL/min/kg)
1
1a
1b
1c
1d
1e
1f
4-ClPh-
4-ClPh-
3-i-PrPh-
2-MeS(O2)fur-5-yl
0.01
0.006
0.0012
0.003
>1.0
>10
0.24
f
2
92
65
>95
>95
0.27
0.43
74.3
60.0
1126
1514
3
benzofur-6-yl 2-MeS(O2)fur-5-yl
0.096
0.20
4
4-ClPh-
4-ClPh-
4-ClPh-
3-MeS(O2)Ph-
2-MeS(O2)Ph-
4-MeS(O2)Ph-
5
6
0.25
7
1g
1h
1i
benzofur-6-yl 3-MeS(O2)Ph-
0.009
0.80
0.074
71
>95
0.78
139.2
705
8
benzofur-6-yl 2-Cl-3-MeS(O2)Ph-
benzofur-6-yl 4-Cl-3-MeS(O2)Ph-
benzofur-6-yl 5-Cl-3-MeS(O2)Ph-
benzofur-6-yl 6-Cl-3-MeS(O2)Ph-
benzofur-6-yl 5-F-3-MeS(O2)Ph-
benzofur-6-yl 3-MeS(O2)Pyrid-5-yl
benzofur-6-yl ( )-3-MeS(O)Pyrid-5-yl
benzofur-6-yl 3-EtS(O2)Ph-
9
0.12
2.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1j
0.01
0.20
1k
1l
0.12
0.01
0.26
0.032
0.050
0.18
>10
0.20
0.64
>10
0.49
5.6
>95
>95
>95
>95
>95
>95
0.65
0.62
0.27
80.5
73.5
1189
1277
753
1m
1n
1o
1p
1q
1r
0.039
0.057
0.002
0.20
121.1
benzofur-6-yl 3-i-PrS(O2)Ph-
benzofur-6-yl 3-NH2S(O2)Ph-
benzofur-6-yl 3-MeNHS(O2)Ph-
benzofur-6-yl 3-Me2NS(O2)Ph-
benzofur-6-yl 3-Me2P(O)Ph-
0.004
0.013
0.010
0.058
0.012
0.010
0.014
71
>95
>95
1.03
0.37
34.4
37.0
2431
2261
1s
1t
>95
1u
1v
1w
benzofur-6-yl 3-MeC(O)Ph-
benzofur-6-yl 3-(R)-MeC(OH)Ph-
benzofur-6-yl 3-(S)-MeC(OH)Ph-
4.0
0.94
a
b
c
The IC50 value is an average of three titrations with eight concentration points. Human serum. Human liver microsomes. Data are shown as %
d
e
remaining. Rat liver microsomes. Data are shown as % remaining. PK experiments were carried out using a group of three male Sprague−Dawley
rats administrated intravenously with a single dose of 5 mg/kg of a testing article. Not determined.
f
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ACS Medicinal Chemistry Letters
Letter
entries 8, 9, and 11) are not well tolerated. The compound
bearing a 3-methylsulfonylpyrid-5-yl residue (1m, entry 13)
demonstrated comparable potency to 1g. Additionally, a
methylsulfoxide residue (1n, entry 14) can substitute the
methylsulfonyl moiety without affecting the potency in the
presence of 10% HS.
mean Schirmer's tear test (STT) values from 3.4 mm during
week 1 to 5.8 mm at week 12 (p < 0.025). This result compared
favorably with the improvement of STT values observed after
the treatment of canine KCS with either 1 or 2% topical
solution of cyclosporine.27,28
With these encouraging preclinical data, 1g was nominated as
SAR 1118 for clinical development. In a randomized, double-
masked, placebo-controlled, dose-escalation phase I human
clinical study,29 SAR 1118 was topically administered as 0.1,
0.3, 1.0, and 5.0% PBS solutions, respectively. SAR 1118
ophthalmic solution appears to be safe and well tolerated up to
5.0% TID. PK analysis showed maximum plasma concen-
trations of SAR 1118 were <5 nM and did not affect circulating
levels of CD3, CD4, or CD8 T-cells, suggesting a lack of
systemic exposure. More importantly, in a recent “proof-of-
concept” phase II human clinical trial in treatment of dry eye,
SAR 1118 demonstrated dose-dependent significant improve-
ments (p < 0.05) in inferior corneal staining over 12 weeks of
treatment. Also, a statistically significant (p < 0.05) increase in
tear production determined by STT and an improvement in
visual-related functions were observed 2 weeks postdose,
demonstrating an early onset of action.30
In summary, we have successfully discovered a potent LFA-
1/ICAM-1 antagonist (SAR 1118) and specifically developed it
into an ophthalmic solution for treating dry eye. Human clinical
data of SAR 1118 have demonstrated that a compound
possessing great potency against the biological target, good
intrinsic solubility, poor oral bioavailability, and fast clearance
can also be developed into a safe and efficacious ophthalmic
treatment. Lately, a pivotal phase III human clinical trial of SAR
1118 in treatment of dry eye (OPUS-1) has commenced.
Important data generated from this critical clinical trial will be
reported in due course.
Replacing the methyl (1g, entry 7) with an ethyl (1o, entry
15) is tolerated; however, a bulkier iso-propyl (1p, entry 16) is
detrimental to the potency in the assay with or without HS.
Moreover, there was a little shift of the potency in the assay
without HS when the methyl was substituted by a more polar
residue (1q−s, entries 17−19). However, when 10% HS was
present, weaker potency was obtained. Assuming the polarity of
sulfonyl (SO) or sulfoxide (S−O) moiety was important to
retain a low serum shift, analogues bearing phosphine oxide
(PO) (1t, entry 20), carbonyl (CO) (1u, entry 21), or
alcohol (C−OH) (1v−w, entries 22−23) were also synthe-
sized, respectively. Unfortunately, inferior potency of these
analogues to 1g was observed in the assay with 10% HS.
Further biological evaluations demonstrated that 1g has
strong inhibition of Jurkat T-cell attachment to ICAM-1 (IC50
= 2.98 nM), lymphocyte activation, and the release of
inflammatory cytokines.22 In particular, releases of inflamma-
tory cytokines, such as interferon γ (IFNγ), macrophage
inflammatory protein-1α (MIP-1α), interleukin-1α (IL-1α), IL-
1β, IL-6, and IL-10, which well correlate with the clinical
severity of human KCS when present in tears, are strongly
inhibited.23
Subsequently, a number of potent compounds, including
1b−c, 1g, 1l−n, 1q, and 1t, were selected for ADME
evaluations. These compounds have good metabolic stability
in both human and rat liver microsomes. Rat iv PK studies
revealed that these analogues have short half-lives, fast
clearances, and low to moderate systemic exposure levels.
Among these compounds, 1g has the fastest clearance and
lowest exposure level. Moreover, 1g exhibited a good in vitro
safety profile, such as being negative in the Ames test and
having low potency in both cytochrome P450 (CYP) inhibition
(3A4, IC50 >20 μM, and 2C9, IC50 = 3.0 μM) and the human
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic scheme and analytical data, including XRPD, TGA,
1
DSC, FT-IR, ESI-MS, H and 13C NMR spectra, elemental
analysis, and solubility of SAR 1118, and detailed descriptions
of HuT 78 and Jurkat T-cell adhesion assays. This material is
available free of charge via the Internet at http://pubs.acs.org.
̀
ether-a-go-go-related gene (hERG) (patch clamp, IC50 >20
μM) assays.
A 14C-labeled 1g at the carbonyl of the central THIQ residue
was topically administered as an ophthalmic solution to both
rats24 and dogs22 to evaluate the corresponding ocular PK
profile. Maximal concentrations with good exposure levels were
achieved 30 min postdose in all ocular tissues, particularly in
bulbar conjunctiva, palpebral conjunctiva, and cornea, of these
two species, while having quick initial and slow terminal
elimination rates by tears. As expected, low exposure levels
were detected in the plasma.
The sodium salt of 1g is freely soluble in phosphate-buffered
saline (PBS) to a concentration of ≥200 mg/mL. This
solubility allows for formulations with a concentration up to
100 mg/mL (10%), which are isotonic with human tears at
approximately 300 mOsmol/L.25 To maintain the ophthalmic
solution at physiological pH values in animal and human
studies, the highest dosing strength used was up to 50 mg/mL
(5%).
AUTHOR INFORMATION
Corresponding Author
*Tel: 415-655-7567. Fax: 415-255-7661. E-mail: mzhong@
presidiopharma.com (M.Z.). Tel: 650-416-7560. Fax: 650-588-
5330. E-mail: gadek@pacbell.net (T.R.G.).
■
Present Address
§Presidio Pharmaceuticals, Inc., 1700 Owens Street, Suite 585,
San Francisco, California 94158, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
SAR 1118 and its related LFA-1 program are exclusive assets of
SARcode Bioscience, Inc. We thank SARcode Bioscience, Inc.,
for its authorization on this publication.
To assess the in vivo efficacy and safety, a 1% PBS solution of
a
1g without ocular lubricating agents26, was topically
ADDITIONAL NOTE
Most drugs tested for clinical efficacy in dry eye contain
lubricating components to ameliorate patients' clinical
symptoms, including the sensation of grittiness or pain with
■
a
administered thrice daily (TID) for 12 weeks for treating
dogs diagnosed with idiopathic KCS. Compound 1g was well
tolerated and showed significant efficacy with the increase of
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ACS Medicinal Chemistry Letters
Letter
LFA-1/ICAM-1 antagonists. Bioorg. Med. Chem. Lett. 2011, 21, 307−
310.
blinking. In many cases, these lubricating components exhibit
significant benefit in both clinical symptoms and signs and
therefore could mask the real effect of a testing drug. For
example, Restasis contains lubricating components, such as
glycerin, castor oil, polysorbate 80, and carbomer copolymer
type A. Its drug-free version is available as Refresh to provide
symptomatic relief to dry eye sufferers. Moreover, it took 6
months of treatment for cyclosporine (0.05%) formulated as an
emulsion with lubricating components to show statistically
significant improvement over the vehicle alone.26
(17) Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S.;
Marsters, J. C. Jr.; Paris, K. J.; Pare, D. A.; Reynolds, M. E.; Ladner, C.;
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