Structure-activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.11.014

This letter describes the structure-activity relationship (SAR) of the 'right-wing' α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified

Full text of DOI:10.1016/j.bmcl.2010.11.014

Bioorganic & Medicinal Chemistry Letters 21 (2011) 307–310
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship (SAR) of the
a-amino acid residue of potent
tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists
⇑
Min Zhong , Emily J. Hanan, Wang Shen, Minna Bui, Michelle R. Arkin, Kenneth J. Barr, Marc J. Evanchik,
Ute Hoch, Jennifer Hyde, 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 structure–activity relationship (SAR) of the ‘right-wing’ a-amino acid residue of
potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted hetero-
Received 28 September 2010
Revised 26 October 2010
Accepted 1 November 2010
Available online 5 November 2010
aryl-bearing -amino acids have been identified as replacements of the ‘right-wing’ (S)-2,3-diaminoprop-
a
anoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human
serum has also been achieved.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
LFA-1/ICAM-1 antagonist
Tetrahydroisoquinoline
a-Amino acid
Structure–activity relationship
(S)-2,3-Diaminopropanoic acid replacement
The interaction between leukocyte function-associated antigen-
1 (LFA-1, Lb2, CD11a/CD18) and intercellular adhesion molecule-
of in vivo efficacy. As part of the efforts to address such an issue,
we performed extensive SAR studies of the ‘right-wing’ amino acid
residue of THIQ-derived LFA-1/ICAM-1 antagonists. Herein, we re-
port the identification of novel (S)-substituted heteroaryl-bearing
a
1 (ICAM-1, CD54) supports inflammatory and specific T-cell regu-
lated immune responses by mediating cell adhesion, leukocyte
extravasation, migration, antigen presentation, formation of the
immunologic synapse, and augmentation of T-cell receptor signal-
ing.1–3 This interaction has been directly implicated in a wide
range of immunoregulatory disorders,4 such as arthritis, psoria-
sis/atopic dermatitis, graft rejection, and ocular diseases, such as
dry eye and diabetic retinopathy. Therefore, much effort has been
expended in discovering small molecule-based LFA-1/ICAM-1
antagonists as potential therapeutics for treating these dis-
eases.5–10
a-amino acids as replacements of the (S)-2,3-diaminopropanoic
acid (DAP) moiety, which resulted in a significant improvement
of potency in the Hut-78 assay11a in the presence of 10% human
serum.
Schemes 1 and 2 describe synthetic approaches to representa-
tive functionalized L-a-amino acid derivatives, which are intro-
duced onto the THIQ scaffold following our previously reported
protocol.11
Recently, we have disclosed the discovery of a novel series of
potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1
antagonists11 exemplified by 1a,b (Fig. 1), which have demon-
strated good mouse and rat pharmacokinetic (PK) profiles and
in vivo efficacy in a thioglycollate-induced murine peritonitis mod-
el. However, as noted in our previous Letter, further evaluation of
the biological properties of 1a,b and their close analogs revealed
a significant reduction of antagonist activity in the presence of
either human or fetal bovine serum, decreasing their likelihood
⇑
Corresponding author. Address: Presidio Pharmaceuticals, Inc., 1700 Owens
Street, Suite 585, San Francisco, CA 94158, USA. Tel.: +1 (415) 655 7567; fax: +1
(415) 255 7661.
E-mail address: mzhong@presidiopharma.com (M. Zhong).
Figure 1. Representative THIQ-derived LFA-1/ICAM-1 antagonists 1a,b.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.014

308
M. Zhong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 307–310
Scheme 1. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 90% yield; (b) NaN3, DMF, 60 °C, 75% yield; (c) CuI (0.1 equiv), DIEA (0.1 equiv), 3-methylbut-1-yne (2.0 equiv),
CH3CN, rt, 65% yield; (d) 2.0 N HCl in ether, rt, quantitative yield; (e) CuI (0.1 equiv), DIEA (0.1 equiv), isopropyl azide (10 equiv), CH3CN, rt, 75% yield; (f) 4.0 N HCl in dioxane,
rt, quantitative yield; (g) isobutyryl chloride, Pd(PPh3)2Cl2, Et3N, CuI, toluene, N2, 80% yield; (h) NH2NH2, MeOH, 0 °C to rt, 65% yield.
Scheme 2. Reagents and conditions: (a) H2SO4, MeOH, rt; 50 °C; (b) Boc2O, K2CO3, THF/H2O, 56% yield (two steps); (c) m-CPBA, DCM, quantitative yield; (d) 4.0 N HCl in
dioxane, quantitative yield; (e) n-BuLi, ꢀ78 °C, THF; CH3SSCH3, ꢀ78 °C to rt, 55% yield; (f) n-BuLi, ꢀ78 °C, THF; dry DMF, ꢀ78 °C to rt, 65% yield; (g) ( )-N-Boc-
a-
phosphonoglycine trimethyl ester, N,N,N0,N0-tetramethylguanidine, DCM, ꢀ35 °C to rt, 70% yield; (h) (+)-bis (2S,5S)-2,5-dimethylphospholano)benzene(cyclooctadiene)-
rodhium(I) tetrafluoroborate (0.01 equiv), MeOH, 45 psi H2, 75% yield; (i) LiHMDS, LiCl, 2-chloromethyl-5-methanesulfonylthiophene, 0 °C, 70% yield; (j) 1.0 N NaOH, reflux;
Boc2O, NaHCO3, dioxane/H2O, 95% yield; (k) TMSCHN2, DCM, rt, quantitative yield.
As shown in Scheme 1, commercially available functionalized
L
-
corresponding thiophene analog 18 is obtained using an asymmet-
ric alkylation approach reported by Myers et al.15
serine 2 is readily converted to its azide derivative 3, which under-
goes a copper catalyzed [3+2] cycloaddition,12 followed by N-trityl
In our previous Letter,11b we disclosed that THIQ analogs bear-
deprotection to give triazole-bearing
Compound 6, the regio-isomer of 4 is prepared similarly using
functionalized -propargylglycine 5 as the starting material. Com-
pound 5 may also be used in a Pd-catalyzed coupling with isobuty-
ryl chloride to give 7, which is treated with hydrazine, followed by
a
-amino acid methyl ester 4.
ing non-DAP ‘right-wing’ residues, such as L-tryptophan, showed
low micromolar potency in the Hut-78 assay. This result is consis-
tent with previous observations8b with N-benzoyl amino acids-
based LFA-1/ICAM-1 antagonists (Fig. 2) that were thought to have
L
the same binding mode as the THIQ chemotype. Although L-trypto-
N-Boc deprotection to yield pyrazole-containing
derivative 8.
a
-amino acid
phan derivative 1d (Table 1, entry 3) has much weaker affinity in
comparison to its corresponding DAP-bearing analog 1c (entry 2),
it has less peptide characteristic and the potency of this non-DAP
analog could potentially be improved by modifying the indole moi-
ety. As summarized in Table 1, when the free –NH of 1d is acety-
lated, the resulting compound (1e) retains potency (entry 4).
Interestingly, when the free –NH of 1d is capped with a methylsul-
fonyl (–SO2Me) moiety, significant improvement of the potency is
observed (entry 5). However, replacing the –SO2Me residue with a
–SO2NH2 moiety results in a substantial decrease in potency (entry
6). Also, introduction of a methyl group at either C-50 (1i) (entry 8)
or -60 (1j) (entry 9) position of the indole moiety of 1f affords low
nanomolar compounds, comparable to the potency of DAP deriva-
tive 1c in the Hut-78 assay. Methyl substitution at the C-40 position
(1h) (entry 7) is not well tolerated while the substitution at the C-
70 position (1k) (entry 10) seems to retain potency. Unfortunately,
there is still a drastic decrease in potency of these compounds in
the presence of 10% human serum (entries 8–10). Presumably,
the hydrophobic nature of the indole moiety contributes to high
protein binding of the molecule, which is detrimental to potency
in the presence of human serum.
2-Methylsulfonyl-substituted
pared using commercially available 2-mercapto-
the starting material, following a sequence of transformations as
outlined in Scheme 2.11a,13 2-Methylsulfonylfuryl substituted
-ala-
L
-histidine derivative 11 is pre-
L-histidine (9) as
L
nine methyl ester (15) is synthesized using asymmetric hydroge-
nation14 of a dehydrated amino acid intermediate 14, while the
Figure 2. Representative N-benzoyl amino acid derived LFA-1/ICAM-1 antagonists
19a,b.

M. Zhong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 307–310
309
Table 1
SAR of
a
-amino acid residue of the THIQ-derived LFA-1/ICAM-1 antagonists
Entry Compd R1
R2
Hut-78 IC50
M)
Hut-78-10% HSb IC50
(lM)
Rat iv PKc
a
(
l
t1/2
CL (mL/min/ AUC (h ng/
(h)
kg)
mL)
1
2
1a
1c
6-Benzofuryl
4-Chlorophenyl
–NHCO(thien-2-yl)
–NHCO(thien-2-yl)
0.005
0.022
0.95
1.5
3.0
1.4
3.2
31
5495
580
d
3
4
5
6
7
1d
1e
1f
1g
1h
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
R3 = H
0.81
0.82
0.10
>1.0
>1.0
—
—
25
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
R3 = –Ac
R3 = –SO2Me
R3 = –SO2NH2
R3 = –SO2Me;
40-Me
8
1i
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
R
3 = –SO2Me;
0.026
11
25
25
—
—
—
—
—
—
—
—
—
50-Me
3 = –SO2Me;
60-Me
3 = –SO2Me;
70-Me
9
1j
R
0.039
0.14
10
1k
R
11
12
13
14
15
16
17
18
19
20
21
22
1l
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
2-Benzofuryl
1H-imidazol-4-yl
0.43
0.56
0.17
—
—
—
—
1.0
—
—
—
—
—
—
2.3
—
—
—
—
—
—
—
—
>60
—
—
—
—
—
—
—
—
1412
—
—
—
—
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1-Me-1H-imidazol-4-yl
1-i-Pr-1H-imidazol-4-yl
1-Ph-1H-imidazol-4-yl
1-i-Pr-1H-1,2,3-triazol-4-yl
4-i-Pr-1H-1,2,3-triazol-1-yl
5-i-Pr-1H-pyrazol-3-yl
5-i-Pr-thiazol-2-yl
>1.0
0.059
0.31
0.25
>1.0
0.01
0.005
0.019
0.007
—
3-i-Pr-phen-3-yl
>10
0.19
0.95
0.26
1-i-Pr-1H-1,2,3-triazol-4-yl
1-i-Pr-1H-1,2,3-triazol-4-yl
1-i-Pr-1H-1,2,3-triazol-4-yl
—
0.97
—
—
26
—
—
3680
—
6-Benzofuryl
2-Pyrazolo[1,5-
a]pyridyl
23
1x
6-Benzofuryl
2-Methylsulfonyl-1H-
imidazol-5-yl
0.030
0.56
—
—
—
24
25
26
1y
1z
6-Benzofuryl
6-Benzofuryl
6-Benzofuryl
2-Methylsulfonylfur-5-yl
2-Methylsulfonylthien-5-yl
1-Methylsulfonylpyrrolid-
3-yl
0.0012
0.15
1.0
0.096
—
—
0.43
—
—
60
—
—
1514
—
—
1a
a
b
c
The IC50 value is an average of three titrations with eight concentration points.
Human 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
Burdick et al. reported that their
parable potency to its corresponding
L
-histidine derivative has com-
1p and 1v are rapidly cleared in rat. Compound 1p does have a rea-
sonable half life (t1/2 = 2.3 h), but its clearance is greater than the
liver blood flow of rat. Similar to the pair of DAP derivatives 1a (en-
try 1) and 1c (entry 2), 1v demonstrates lower CL and higher area
under curve (AUC) as compared to 1p. It should be noted that the
overall rat iv profile of 1v is inferior to that of the corresponding
DAP analog 1a.
L
-tryptophan analog (Fig. 2,
19a vs 19b).8b As expected, this trend was also observed on our
THIQ series compounds (1d vs 1l) (entries 3 and 11). Next, several
readily available N-substituted THIQ analogs were prepared to ob-
tain preliminary SAR on the imidazole moiety (entries 12–14),
which led to the identification of N-isopropyl (-iPr) substituted
analog 1n (entry 13) with slightly improved affinity relative to 1l
(entry 11). Subsequently, several 1n close derivatives were pre-
pared by replacing the imidazole residue with other five- and
six-membered aromatic moieties, such as triazole, thiazole, pyra-
zole, and phenyl (entries 15–19). Interestingly, triazole-bearing
analog 1p (entry 15) and phenyl-bearing analog 1t (entry 19) dem-
onstrated significant improvement of potency in the Hut-78 assay.
However, only 1p retained good activity in the presence of 10% hu-
man serum, while 1t completely lost its potency under the same
condition. Moreover, both 1p and its 2-benzofuryl (1u), 6-benzofu-
ryl (1v) and 2-pyrazolo[1,5-a]pyridyl (1w) analogs (entries 20–22)
have comparable or improved potency to the corresponding DAP
derivatives 1a (entry 1) and 1c (entry 2) in both assays.
The SAR of N-SO2Me L-tryptophan derivatives and -iPr substi-
tuted azole-bearing analogs led us to explore –SO2Me substituted
heteroaryl analogs. As summarized in Table 1, 2-methylsulfonylim-
idazole analog 1x (entry 23) shows comparable potency to N-iPr
substituted triazole derivative 1v (entry 21) in the Hut-78 assay
in the presence of 10% human serum. Interestingly, the correspond-
ing furan analog 1y (entry 24) demonstrates a significant improve-
ment in potency17; however, the corresponding thiophene analog
1z (entry 25) is less active relative to both 1x and 1y. Moreover,
the non-aromatic N-SO2Me substituted pyrrolidine analog (1a) (en-
try 26) is much less potent than the corresponding aromatic ones.
Similar to 1v, 1y is stable in both rat and human liver microsomes.16
However, a rat iv PK study shows that 1y has a short t1/2 and high CL
with total exposure similar to 1p (entry 15) as indicated by AUC.
In summary, we have successfully identified a number of DAP
replacements bearing functionalized heteroaryl moieties during
Compounds 1p (entry 15) and 1v (entry 21) were further eval-
uated to determine their preliminary pharmacokinetic properties.
Despite evidence of good stability in rat liver microsomes,16 both

310
M. Zhong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 307–310
DeVries, P.; Leitza, S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von Geldern, T.
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THIQ-derived LFA-1/ICAM-1 antagonists. Several compounds pos-
sessing these amino acids have good potency in the Hut-78 assay
in the presence of 10% human serum. However, these potent
LFA-1/ICAM-1 antagonists generally have inferior PK profiles in
rat comparing to the corresponding DAP derivatives. Future work
will be focused on optimizing analogs bearing the –SO2Me substi-
tuted DAP replacements and potentially applying this type of com-
pounds in treatment of human immunoregulatory disorders,
which will be reported in due course.
Acknowledgments
The authors thank Drs. Thomas R. Gadek and Daryl B. Winter of
SARcode, Inc. for helpful discussions and Stuart Lam, Thomas
Webb, and Alex Hsi for their assistance on preparative HPLC
purifications.
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13. For the transformation of 9–10, it can be done through either a two-step
sequence as shown in Scheme
2 or a three-step sequence by initially
methylating the –SH with MeI in the presence of K2CO3 in acetone, followed
by esterfication and Boc-protection. For H2SO4 mediated methylation of –SH in
MeOH, also see, Shimizu, M.; Shimazaki, T.; Kon, Y.; Konakaharab, T.
Heterocycle 2010, 81, 43.
14. (a) Chou, S.-S. P.; Shen, C.-H. Tetrahedron Lett. 1997, 38, 6407; (b) Burk, M. J.;
Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125; (c)
Masquelin, T.; Broger, E.; Müller, K.; Schmid, R.; Obrecht, D. Helv. Chim. Acta
1994, 77, 1395.
15. (a) Chou, S.-S. P.; Sun, D.-J.; Huang, J.-Y.; Yang, P.-K.; Lin, H.-C. Tetrahedron Lett.
1996, 37, 7279; (b) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J. Org. Chem.
1999, 64, 3322.
16. Compounds 1p, 1v and 1y were evaluated in liver microsomal stability assays.
The tested compounds were incubated with rat or human liver microsomes in
the presence of NADPH and MgCl2 solution. Samples were taken at 0, 30, and
60 min three time points and tested on LC/MS. The data were reported as a
ratio of the peak area at 30 min or 60 min relative to the one at 0 min.
Lidocaine and Dextromethorphan were used as positive controls. 1p: 92% at
30 min in human liver microsomes (HLM); 1v: >95% at 30 min in rat liver
microsomes (RLM) and 86% at 30 min in HLM; and 1y: >65% at 30 min in RLM
and >95% at 30 min in HLM.
17. In general, analogs bearing the ‘right-wing’ amino acid moiety of 1y and
various ‘left-wing’ residues show better potency relative to the corresponding
DAP analogs in either the Hut-78 or Staphylococcal Enterotoxin B (SEB)-
stimulated T-cell activation assay in the presence of either human or fetal
bovine serum. The data are not shown.
7. (a) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.;
Okasinski, G. F.; von Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med.
Chem. 2000, 43, 4025; (b) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.;