Biaryl substituted hydantoin compounds as TACE inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.06.134

We disclose further optimization of hydantoin TNF-α convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K_i<

Full text of DOI:10.1016/j.bmcl.2010.06.134

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5286–5289
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biaryl substituted hydantoin compounds as TACE inhibitors
a
a
a
a
a
Wensheng Yu a, , Ling Tong , Seong Heon Kim , Michael K. C. Wong , Lei Chen , De-Yi Yang ,
Bandarpalle B. Shankar a, Brian J. Lavey a, Guowei Zhou a, Aneta Kosinski a, Razia Rizvi a, Dansu Li b,
Robert J. Feltz a, John J. Piwinski b, Kristin E. Rosner b, Neng-Yang Shih b, M. Arshad Siddiqui b,
Zhuyan Guo c, Peter Orth c, Himanshu Shah d, Jing Sun d, Shelby Umland d, Daniel J. Lundell d,
Xiaoda Niu d, Joseph A. Kozlowski a
*
a Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
b Department of Medicinal Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States
c Department of Drug Design, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
d Department of Bone, Respiratory, Immunology, and Dermatology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We disclose further optimization of hydantoin TNF-
a convertase enzyme (TACE) inhibitors. SAR with
Received 18 March 2010
Revised 23 June 2010
Accepted 28 June 2010
Available online 01 July 2010
respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin
compounds was shown to have sub-nanomolar Ki, good rat PK, and good selectivity versus MMP-1, -2, -3,
-7, -9, and -13.
Ó 2010 Published by Elsevier Ltd.
Keywords:
TACE
TNF-a convertase
TACE inhibitor
Hydantoin
Hydantoin zinc ligand
Anti-TNF
Rheumatoid arthritis
Tumor necrosis factor-
mune response. Overproduction of TNF-
a
(TNF-
a
) is a key cytokine in innate im-
mediates a variety of
autoimmune diseases including rheumatoid arthritis, psoriasis,
of biaryl groups to occupy the non-prime region of the TACE active
site.
a
The X-ray structure of 1 suggests that the non-prime region of
the protein is pretty open and could tolerate other substitutions
(Fig. 2). To explore this idea, a set of compounds with additional
substitution on the phenyl group was prepared as described in
Scheme 1. Compound 3 was converted to the desired amine 4
through sequential Boc protection, hydantoin formation, and Boc
deprotection. Compound 7 was prepared from 5 by sequential
methylation and bromination. Alkylation of amine 4 with benzyl
and Crohn’s disease.1 The reduction of circulating TNF-
a levels by
biologic drugs, such as EnbrelÒ and RemicadeÒ, is a successful
treatment for several inflammatory diseases. As a result, discovery
of a cost-effective, orally active small molecule drug that could
modulate TNF-
An approach amenable to small molecule discovery is the regu-
lation of TNF- levels via the inhibition of TNF- converting en-
zyme (TACE). TACE converts the 26-kDa transmembrane bound
pro-TNF-
to the mature 17-kDa soluble form of TNF.2,3 TACE
a levels is of high interest.
a
a
a
inhibitors are generally classified as hydroxamates4 or non-
hydroxamates.5 Our program has been focused on the non-
hydroxamate class of TACE inhibitors. We recently disclosed a ser-
ies of tartaric acid based TACE inhibitors6 and a series of hydan-
toin-based TACE inhibitors (Fig. 1).7 Herein we report further
optimization of the hydantoin TACE inhibitors by the introduction
F
O
O
OMe
OMe
N
N
HN
HN
N
H
O
O
O
O
N
H
N
H
1
2
TACE Ki = 6 nM
TACE Ki = 0.8 nM
* Corresponding author.
E-mail address: wensheng.yu@merck.com (W. Yu).
Figure 1. Hydantoin-based TACE inhibitors 1 and 2.
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.06.134

W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5286–5289
5287
Table 1
TACE Ki of hydantoin TACE inhibitors
R1
4'
2'
R2
3'
O
R4
6
R3
N
HN
O
O
N
H
Compd
R1
R2
H
R3
H
R4
TACE Kia (nM)
(R)-13
OMe
OMe
3
7
O
N
(R)-14
(R)-15
(R)-16
H
H
H
H
H
H
O
Figure 2. X-ray structure of 1 (3LE9) bound to the active site of TACE.
N
Br
OMe
OMe
8
6
Br
O
a - c
NH2 ·HCl
HN
O
NH2 ·HCl
O
O
NH
4
O
3
N
N
R2
R2
R2
O
(R)-17
(R)-18
H
H
H
H
F
8
6
e
f
d
CO2CH3
CO2H
CO2CH3
O
N
OMe
Br
O
5
6
7
( )-19
( )-20
H
H
H
OPh
OPh
H
F
F
29
27
Br
Br
O
a
The compounds were tested for their inhibition of the cleavage of a pro-TNF-
peptide catalyzed by TACE.9
a
R2
R2
g, h
O
N
N
HN
R1
HN
O
O
8
O
N
N
H
bromide 7 gave 8 in moderate yield. Compound 8 was protected as
a SEM ether and the enantiomers were separated by HPLC on a
Chiralpak AD column.8 The desired (R)-enantiomer 9 was coupled
with R1B(OH)2, R1OH, amines, or amides under various coupling
conditions to give 10 in moderate to good yield. The SEM group
was deprotected by sequential treatment with HCl in MeOH, then
triethylamine to give 11 in moderate yield.
An alternative way to prepare 11 is shown in Scheme 2. Com-
pound 9 was converted to boronate 12 via Pd-catalyzed reaction
with bis(pinacolato)diboron. Compound 11 was obtained via vari-
ous coupling reactions of 12 with R1Br or R1I followed by deprotec-
tion of the SEM group.
9
SEM
R1
O
O
R2
j
R2
i
N
N
HN
HN
O
O
O
N
O
N
H
SEM
11
10
Scheme 1. Reagents and conditions: (a) (Boc)2O, DCM, Et3N, rt, 16 h, 100%; (b) KCN,
(NH4)2CO3, EtOH/H2O (1:1), 70 °C, 24 h, 86%; (c) HCl, MeOH, 16 h, 90%; (d) MeI,
Cs2CO3, DMF, rt, 16 h, 99%; (e) NBS, benzoyl peroxide, CCl4, 80 °C, 4 h, 99%; (f) 4,
DIPEA, DMF, rt, 16 h, 68%; (g) SEMCl, DIPEA, DMF, rt, 5 h, 85%; (h) HPLC separation;
(i) R1B(OH)2, Pd(dppf)2Cl2ꢀCH2Cl2, K2CO3, CH3CN, H2O, 50–90%, or R1OH, CuI,
Cs2CO3, 2,2,6,6-tetramethyl-3,5-heptanedione, NMP, 140 °C, 15 h, 20–80%; or
pyrrolidin-2-one, Pd(dba)2, Xantphos, Cs2CO3, dioxane, 100 °C, 16 h, 70%; (j) HCl,
MeOH, 90 °C, 16 h, then TEA, 46–80%.
The TACE activities of some compounds prepared following
Scheme 1 or Scheme 2 are shown in Table 1. The 40-cyclopentoxy
analog 13 showed single-digit nanomolar activity. Replacement
of cyclopentyl by pyridyl 14 retained the activity. When a large
group such as isoquinolin-6-yloxy 15 was incorporated, TACE
activity was maintained relative to 14. N-linked substitution, such
as found in the 40-morpholinyl analog 16 and the
c-lactam 17, was
also tolerated. Likewise, the carbonyl-linked tertiary amide 18 pos-
sessed similar activity. These results suggest that a wide variety of
substituents differing in size and linker atom is permissible at C40.
By contrast, two analogs bearing phenoxy substitution at either C20
(19) or C30 (20) showed slightly reduced activity relative to the
preceding compounds.
O
O
B
O
R2
b, c
a
11
9
N
HN
Thus it seems that C40 substitutions can offer potent TACE
inhibitors. Examination of the X-ray structure of 1 suggested that
the substituent at the C40 position may interact with the methylene
chain of Lys315. To further test this hypothesis, more C40-substi-
tuted analogs with linear biaryl groups were prepared (Table 2).
The linear arrangement of the biaryl groups can maximize the
O
O
N
SEM
12
Scheme 2. Reagents and conditions: (a) Bis(pinacolato)diboron, Pd(dppf)2Cl2ꢀ
CH2Cl2, KOAc, dioxane, 125 °C, 2 h; (b) RBr or RI, Pd(dppf)2Cl2ꢀCH2Cl2, K2CO3,
CH3CN, H2O; (c) HCl, MeOH, 90 °C, 16 h, then TEA.

5288
W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5286–5289
analog 23 is less active. The 40-methyl benzoate analog 24 is less
Table 2
TACE Ki of biaryl substituted hydantoin TACE inhibitors
active than the corresponding amide analog 25. Since the biphenyl
group occupies the non-prime S1 pocket which is mostly solvent-
exposed, a more hydrophilic substitution might be preferred. Pyr-
idyl analogs (26–28) were prepared and they are 3- to 4-fold more
potent than the biphenyl analogs 21 and 22. The X-ray structure of
27 bound to the TACE active site (Fig. 3) shows that the phenyl–
pyridyl group occupies the shallow S1 pocket and forms hydropho-
bic contacts to residues Val314, Lys315, Thr347, and Leu350. 2-
Aminopyridine analog 29 is slightly less active than the 40-pyridyl
analog 28. Pyridone analogs 30 and 31 are more potent than the 30-
pyridyl analog 27. Other heterocyclic substitutions (e.g., R1 = 50-
pyrimidinyl (32), 20-thiazolyl (33), and 20-pyrazinyl (34)) all show
good potency. 6-F analogs 35 and 36 show good potency as well.
Addition of one or two methyl groups to the heteroaryl groups
are well tolerated (36–38). A hydantoin analog 39 also has good
TACE activity.
R1
O
4'
R2
6
N
HN
O
O
N
H
Compd
R1
4-Cl-phenyl
2,4-Di-F-phenyl
4-CF3-phenyl
R2
TACE Ki (nM)
21
22
23
OMe
2
2
18
F
F
CO2CH3
24
OMe
9
CONH2
25
OMe
3
26
27
28
2-Pyridinyl
3-Pyridinyl
4-Pyridinyl
OMe
OMe
OMe
0.5
0.8
0.6
N
29
30
OMe
F
1.4
0.2
NH2
O
H
N
H
N
O
31
F
0.1
Cl
32
33
34
35
5-Pyrimidinyl
2-Thiazolyl
2-Pyrazinyl
3-Pyridinyl
O
OMe
OMe
OMe
F
0.9
0.6
1.2
1.0
N
36
F
0.5
Figure 3. X-ray structure of 27 (3LEA) bound to the active site of TACE.
N
N
37
38
OMe
OMe
2.0
0.5
Table 3
N
Rat pharmacokinetic parameters of 27, 37, and 38
CH3
27
37
38
O
iv
Dose (mg/kg)
AUC ( M h)
T1/2 (h)
Cl (L/h/kg)
Vss (L/kg)
3
3
3
NH
l
19.0
4.3
6.2
0.3
36.2
4.4
3.3
0.3
21.0
4.4
5.5
0.3
39
OMe
2.6
O
N
H
H3C
CH3
N
40
41
OMe
OMe
2.0
3.0
po
Dose (mg/kg)
10
9.1
2.96
0.58
14.1
10
22.2
4.45
2.00
18.0
10
13.0
3.3
1.7
19.0
N
AUC (
l
l
M h)
M)
Cmax
(
N
Tmax (h)
F%
CH3
N
N
42
43
44
F
0.8
2.0
31
Table 4
OMe
OMe
Selectivity data of compounds 27, 37, and 38a
NH
N
S
Compounds
27
37
38
N
TACE (nM)
0.77
655
—
3.61
17,400
124
155
25
0.88
718
24
430
>40,000
122
202
19
187
0.52
1740
86
434
30,000
212
194
36
MMP-1 (nM)
MMP-2 (nM)
MMP-3 (nM)
MMP-7 (nM)
MMP-9 (nM)
MMP-13 (nM)
MMP-14 (nM)
ADAM10 (nM)
N
O
45
46
OMe
F
28
10
N
N
N
N
216
253
a
The compounds were tested for their inhibition of the cleavage of peptide
substrates catalyzed by various MMPs.
interaction with Lys315 side chain. Halogenated phenyl analogs 21
and 22 gave single-digit nanomolar activity. The 40-CF3-phenyl

W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5286–5289
5289
To further explore the substitution patterns that could be toler-
References and notes
ated, compounds with larger substituents were prepared. 2-
Methyl-2H-indazolyl (40) and 1-methyl-1H-pyrrolo[2,3-b]pyridyl
(41) analogs displayed single-digit nanomolar activity. The quinoli-
nyl analog 42 as well as the non-fused, linear triaryl analog 43
were also potent. However, compounds 44–46, which have a
non-linear structure, are less potent since vander-Waals interac-
tions to Asp313 and Lys315 are presumably disrupted.
The data shown in Table 2 shows that multiple heterocycles are
well tolerated and a large number of compounds are found to have
sub-nanomolar activity. The human whole blood activity of some
of these compounds was tested.10 They showed an improved IC50
compared with our earlier hydantoin TACE inhibitors.7 For exam-
ple, the human whole blood IC50 of 16, 27, 28, 32, and 39 ranged
1. (a) Cerretti, D. P. Biochem. Soc. Trans. 1999, 27, 219; (b) Vassalli, P. Annu. Rev.
Immunol. 1992, 10, 411.
2. Black, R. A.; Rauch, C. T.; Kozlosky, C. J.; Peschon, J. J.; Slack, J. L.; Wolfson, M. F.;
Castner, B. J.; Stocking, K. L.; Reddy, P.; Srinivasan, S.; Nelson, N.; Boiani, N.;
Schooley, K. A.; Gerhart, M.; Davis, R.; Fitzner, J. N.; Johnson, R. S.; Paxton, R. J.;
March, C. J.; Cerretti, D. P. Nature 1997, 385, 729.
3. (a) Bemelmans, M. H. A.; van Tits, L. J. H.; Buurman, W. A. Crit. Rev. Immunol.
1996, 16, 1; (b) Aggarwal, B. B.; Natarajan, K. Eur. Cytokine Netw. 1996, 7, 93.
4. For a recent review of TACE inhibitors, see DasGupta, S.; Murumkar, P. R.;
Giridhar, R.; Yadav, M. R. Bioorg. Med. Chem. 2009, 17, 444.
5. (a) Sheppeck, J. E., II; Gilmore, J. L.; Yang, A.; Chen, X.-T.; Xue, C.-B.; Roderick, J.;
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2007, 17, 1413; (b) Sheppeck, J. E., II; Gilmore, J. L.; Tebben, A.; Xue, C.-B.; Liu,
R.-Q.; Decicco, C. P.; Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2007, 17, 2769; (c)
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C. P.; Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2007, 17, 1408.
from 0.5 to 1.3
l
M.
6. Rosner, K. E.; Guo, Z.; Orth, P.; Shipps, G. W., Jr.; Belanger, D. B.; Chan, T. Y.;
Curran, P. J.; Dai, C.; Deng, Y.; Girijavallabhan, V. M.; Hong, L.; Lavey, B. J.; Lee, J.
F.; Li, D.; Liu, Z.; Popovici-Muller, J.; Ting, P. C.; Vaccaro, H.; Wang, L.; Wang, T.;
Yu, W.; Zhou, G.; Niu, X.; Sun, J.; Kozlowski, J. A.; Lundell, D. J.; Madison, V.;
McKittrick, B.; Piwinski, J. J.; Shih, N.-Y.; Siddiqui, M. A.; Strickland, C. O. Bioorg.
Med. Chem. Lett. 2010, 20, 1189.
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D. J.; Niu, X.; Piwinski, J. J.; Popovici-Muller, J.; Rizvi, R.; Rosner, K. E.; Shankar,
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The rat pharmacokinetic parameters of 27, 37, and 38 were pro-
filed. All were found to have excellent AUCs and moderate bioavail-
ability as shown in Table 3.
The selectivity data of 27, 37, and 38 versus a group of MMP and
ADAM enzymes are listed in Table 4. These compounds have good
selectivity versus MMP-1, -3, -7, -9, -13, and ADAM10, but their
selectivity versus MMP-1 and -14 was lower.
In summary, we have explored and optimized the SAR with re-
spect to the non-prime region of the TACE active site. A series of
biaryl hydantoin TACE inhibitors was found to have sub-nanomo-
lar activity. Several members of this series also have good rat PK
and good selectivity versus MMP-1, -3, -7, -9, -13, and ADAM10.
The human whole blood activity of this series of TACE inhibitors
is improved relative to our early hydantoin TACE leads.7 Further
optimization of the human whole blood activity of our lead hydan-
toin TACE inhibitors will be reported in future publications.
8. For chiral HPLC separation conditions, see patent: Yu, W. et al. WO
2007084415.
9. Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y. H.; Sun, J.; Lundell, D.; Orth,
P. Arch. Biochem. Biophys. 2006, 451, 43.
10. Human whole blood is diluted 1:1 with serum free medium (RPMI,
glutamine, Pen-Strep, HEPES) and incubated with compound in final
volume of 360 L for 1 h at 37 °C. Forty microliters of LPS (10 g/mL) is then
added. Supernatant is collected after 3.5 h incubation and the concentration of
TNF- is determined by ELISA (R&D Systems).
L-
a
a
l
a