Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases

Article abstract of DOI:10.1016/j.bmcl.2010.10.081

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K_i) as well as excellent activity in human whole blood. These studies led to the discov

Full text of DOI:10.1016/j.bmcl.2010.10.081

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7283–7287
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel TNF-
a
converting enzyme (TACE) inhibitors as potential treatment
for inflammatory diseases
Vinay M. Girijavallabhan a, , Lei Chen a, Chaoyang Dai b, Robert J. Feltz a, Luke Firmansjah b, Dansu Li b,
⇑
Seong Heon Kim a, Joseph A. Kozlowski a, Brian J. Lavey a, Aneta Kosinski a, John J. Piwinski b,
Janeta Popovici-Muller b, Razia Rizvi a, Kristin E. Rosner b, Banderpalle B. Shankar a, Neng-Yang Shih b,
M. Arshad Siddiqui b, Ling Tong a, Michael K. C. Wong a, De-yi Yang a, Liping Yang b, Wensheng Yu a,
Guowei Zhou a, Zhuyan Guo d, Peter Orth d, Vincent Madison d, Hong Bian c, Daniel Lundell c, Xiaoda Niu c,
Himanshu Shah c, Jing Sun c, Shelby Umland c
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 Inflammation, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
d Department of Drug Design, 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:
Our research on hydantoin based TNF-
a converting enzyme (TACE) inhibitors has led to an acetylene
Received 2 September 2010
Revised 14 October 2010
Accepted 15 October 2010
Available online 23 October 2010
containing series that demonstrates sub-nanomolar potency (Ki) as well as excellent activity in human
whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Published by Elsevier Ltd.
Keywords:
Hydantoin
TACE inhibitor
Rheumatoid arthritis
Rheumatoid arthritis is a chronic autoimmune inflammatory
disorder that attacks the joints, often progressing to the destruc-
tion of the particular cartilage and alkylosis of the joints. Biologics,
such as RemicadeÒ and EnbrelÒ, have had success in treating the
the hWBA of the biaryl series, several modifications were made to
the distal ring 2, which is known to project into the solvent ex-
posed S1 pocket of the enzyme.11,9a Most of these modifications
did not enhance the hWBA, therefore, focus was then shifted to
modifications of Ring 1. As shown in Figure 1, an acetylene could
be an intriguing choice as a linker since it projects Ring 2 in a sim-
ilar linear orientation as in the biaryl series and it could also pro-
vide access to other types of functionalities as aryl replacements.
disease by controlling the levels of tumor necrosis factor-
(TNF- ), a major immunomodulatory and proinflammatory cyto-
kine.1 A small molecule drug discovery approach could entail con-
trolling the level of TNF- by inhibiting the TNF- converting
enzyme (TACE/ADAM 17), a metalloproteinase (MMP) known to
cleave the 26-kD membrane-bound form of TNF- to its 17 kDa
a
a
a
a
a
soluble component.2,3 Since musculoskeletal side effects have been
seen with the use of broad spectrum MMPs, our goal was to
achieve a good selectivity profile for any small molecule metallo-
proteinase inhibitor.4–7 Our early research efforts on small mole-
cule TACE inhibitors led to a series of hydantoin compounds.8,9
After extensive efforts to optimize the series, a lead biaryl series
was identified which provided selective sub-nanomolar inhibitors
(Ki). However, these compounds exhibited a significant shift in hu-
man whole blood activity (hWBA) (Fig. 1).10 In an effort to optimize
Ring 2
R
R
Ring 1
O
O
7
4
OMe
6
OMe
N
O
N
5
HN
O
HN
O
O
N
H
N
H
1
Ki = < 1 nM
hWBA = > 1 uM
⇑
Corresponding author.
E-mail address: vinay.girijavallabhan@spcorp.com (V.M. Girijavallabhan).
Figure 1. Development of an acetylene series of inhibitors.
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.10.081

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V. M. Girijavallabhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7283–7287
O
O
O
OMe
OMe
OMe
OMe
a
b
MeO
Br
c
MeO
O
MeO
Br
3
2
4
O
O
OMe
OMe
e
d
N
O
HN
N
O
Br
5
6
7
TMS
OH
NH
OMe
Cl
O
i
h
7
f,g
MeO
MeO
HO
MeO
OMe
NH
NH
OMe
j
O
O
O
O
O
O
10
OMe
O
9
8
11
TMS
O
N
O
N
O
O
OMe
l
k
MeO
N
H
MeO
N
H
O
O
MeO
MeO
12
13
O
N
O
OMe
OMe
Ar
Ar
N
m
O
CO2Me
HN
HN
NH
O
OMe
14
O
15
Scheme 1. Reagents and conditions: (a) trimethylboroxine, Pd(dppf)Cl2,Cs2CO3, dioxane, H2O, 80%; (b) NBS, benzoylperoxide, 98%; (c) 7 M NH3/MeOH, 60 °C, 67%; (d)NaOt-Bu,
THF, DMPU, chloromethylpivalate, 91%; (e) bromotrimethylsilane, DCM, 95%; (f) methyl carbamate, Et2O, 98%; (g) H2SO4, MeOH, 71%; (h) PCl5, CCl4, 96%; (i) bis-
trimethylsilylacetylene, AlCl3, DCM, 0–25 °C, 69%; (j)LiHMDS, THF, 7, À78 °C, 63% then chiral chromatography, Chiralcel OD column; (k) TBAF, THF 95%; (l) Ar-X, Cul,
Pd(PPh3)2Cl2, DIEA, DMF, 80 °C, 60–90%; (m) 7 M NH3/MeOH, 80 °C, 95%.
The first goal was to develop a route that could be used to
synthesize numerous acetylene analogs in a convergent manner.
The 6-OMe lactam which was found to be the optimal piece with
regards to Ki in compound 1 was retained for this study. The
synthesis began with the methylation of methyl 2-bromo-5-
methoxybenzoate 2 using trimethylboroxine under palladium
cross coupling conditions to provide compound 3 (Scheme 1).12
The benzylic position was brominated using NBS and benzoyl per-
oxide and then cyclized to the lactam 5 using ammonia in metha-
nol. Alkylation of the lactam with chloromethylpivalate provided
compound 6, which was then treated with bromotrimethylsilane
to provide compound 7. The synthesis of the amino acid derivative
began with the treatment of glyoxylic acid with methyl carbamate
followed by esterification with sulfuric acid/methanol to provide
compound 9.13 Compound 9 was treated with phosphorus penta-
chloride to produce the 2-chloroglycinate intermediate 10, a stable
white powder that could be stored at room temperature. Reaction
of 10 with bis-trimethylsilyl acetylene and aluminum trichloride
provided the trimethylsilyl-acetylene 11 which was alkylated by
treatment with LiHMDS followed by the addition of the bromo-
methyl lactam 7 to provide compound 12. The two enantiomers
could be separated by HPLC on large scale using a Chiralcel OD
column. The desired enantiomer was subsequently treated with
TBAF to remove the trimethylsilyl group.
As part of the synthetic strategy, the key intermediate 13 could
be coupled to various different aryl halides using standard
Sonagashira reaction conditions to provide compounds of type
14. The final step in the synthesis was the cyclization of the amino
acid derivative to the desired hydantoin using ammonia to provide
target compounds of type 15. This robust synthesis could be used
to synthesize multigram quantities of the desired final products
and provided a versatile method of attaching different aryl/hetero-
aryl groups to the hydantoin series late in the synthesis.
Table 1 displays the TACE Ki/hWBA activities of aryl-acetylene
compounds. Despite their subnanomolar Ki values, compounds
16–23 did not have hWBA in the desired range (Table 1). Since this
part of the molecule projects into the solvent exposed S1 pocket,
the incorporation of polar functionality could potentially improve
the hWBA.14,9a When a nitrile was placed on the 3-position of
the ring (24) we discovered an improvement in both Ki and hWBA.
When the nitrile was converted to the primary amide (25) the Ki
decreased, but the hWBA was similar. Movement of the primary
amide to the other positions of the phenyl ring (26 and 27) dem-
onstrated that the 4- and 3-position were optimal for hWBA.
Though there was an improvement in hWBA in compounds 25
and 26, the Ki was slightly higher than found in compounds 16–
23 which had demonstrated poor hWBA. This divergence in SAR
would prove to be a trend for the program and therefore, hWBA

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7285
Table 1
Table 2
TACE Ki/hWBA of aryl acetylene analogs
TACE Ki/hWBA of acetylene analogs
R
O
R
OMe
O
N
OMe
N
O
HN
O
O
NH
HN
NH
O
Compound
R
Ki (nM)
hWBA (nM)
Compound
R
Ki (nM)
hWBA (nM)
NH
16
17
18
19
20
21
22
23
24
25
26
27
28
29
H
4-F
3-F
2-F
4-OMe
3-iPr
3-Me
2-Me
3-CN
3-CONH2
4-CONH2
2-CONH2
4-CONH-cyclopropyl
4-CH2CONH2
O
0.14
0.26
0.2
0.13
0.41
0.5
784
1675
873
32
0.17
0.19
0.52
751
2965
617
1332
19000
5148
3142
273
302
165
5311
487
139
HN
0.72
2.0
33
34
0.06
0.85
0.56
2.78
2.55
0.42
N
N
10400
NH
N
35
36
0.6
211
240
30
31
0.5
352
621
O
NH
NH2
HN
0.53
2.35
N
37
38
0.62
0.92
220
193
NH
was used as an important criterion for the advancement of com-
pounds.15 N-Alkylation of the amide (28) diminished the hWBA,
but homologation of the primary amide (29) provided a slight
improvement in hWBA.
N
N
N
In order to optimize for hWBA, it was important to examine the
factors that contributed to the improved hWBA of the amides. The
primary amides demonstrated that polar functionality at the 3- or
4-position of the phenyl ring could provide improvements to
hWBA. Given that a primary amide group can act as both a hydro-
gen bond donor and acceptor, it was important to determine which
of these characteristics influenced the hWBA most. When the pri-
mary amide was replaced by a methyl ketone (30) which only
has the ability to accept hydrogen bonds, the hWBA was slightly
diminished. Replacement of the primary amide with the primary
amine 31 displayed an even greater loss in potency. These results
prompted a continuous effort to find alternative polar functional
groups that could lead to enhanced hWBA. One strategy was to re-
place the phenyl/amide functionalities with heteroaryl rings as
well as aryl rings containing polar functionalities. These function-
alities could also be used to further probe whether hWBA is depen-
dent on hydrogen bonding ability and also if basicity is tolerated in
this portion of the molecule.
As shown in Table 2, the hydrogen bond donating indoles 32
and 33 both demonstrated a loss in hWBA. When the hydrogen
bonding ability was completely removed as in indazole 34 there
was a large decrease in hWBA. However, hWBA was improved in
the case of benzimidazole 35 which has the ability to accept hydro-
gen bonds. It was uncertain whether the improvement in hWBA
was due to the hydrogen bond ability of the benzimidazole, thus,
the 2-hydroxybenzimidazole (36) was synthesized and confirmed
N
39
40
0.29
0.61
239
205
195
H
N
N
N
41
42
0.47
0.16
N
OH
N
167
(continued on next page)

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V. M. Girijavallabhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7283–7287
incorporated into the molecules the hWBA was retained. Accord-
Table 2 (continued)
ingly, other non-aromatic basic amines were incorporated and it
was found that amines such as 39–41 also provided good hWBA.
These compounds suggested that basic functionality could be
placed further from the ring and retain hWBA.
Compound
R
Ki (nM)
hWBA (nM)
N
N
N
HO
At this point it was evident that we could consistently achieve
hWBA levels of ꢀ200 nM by adding functionalities with hydrogen
bond accepting potential in close proximity to the 3- or 4-position
of the phenyl ring with the optional presence of basic functional-
ities further from the phenyl ring. However, in desiring to improve
the hWBA even further we decided to return to our most potent
compounds and make adjustments to the hydrogen bonding ability
as well as basicity of functional groups. Since only the 4-position
primary amide displayed hWBA less than 200 nM it was important
to retain that substitution pattern. When the amide was replaced
by the oxime 42 the hWBA was retained. Further introduction of
a basic piperazine component to the structure of oxime 42, which
is capable of hydrogen bond accepting, resulted in the novel ami-
doxime 43 in which a significant improvement in hWBA was ob-
served. Incorporation of a heteroatom, such as in 44, resulted in
only a slight reduction in activity relative to 43.
Replacement of the amidoxime in compound 43 by the analo-
gous oxime 45 demonstrated retention of potency as well. The po-
tent compound 46 was designed as a constrained analog of 43 and
possesses both the basic pyridine nitrogen and the hydrogen bond
accepting group on opposing sides of the same ring. Compound 47
incorporates the piperazine found in 39 to further improve the
hWBA to less than 100 nM.
43
44
45
0.16
20
N
N
N
N
HO
HO
0.18
0.22
87
33
N
N
N
N
HO
46
47
0.07
117
N
N
Of all the compounds synthesized, compound 37 displayed the
best overall profile. It had an encouraging PK in rat, monkey, and
dog and had a reasonable selectivity profile (Fig. 2).
HO
F
0.1
40
In summary, we have developed novel acetylene-based hydan-
toin inhibitors of the TACE enzyme that have excellent Ki and
hWBA. Vast improvements to the hWBA were discovered by add-
ing hydrogen bonding and basic functionalities in the solvent ex-
posed S1 region of the enzyme. These modifications led to the
discovery of compound 37 which has a good selectivity profile
and demonstrates PK in multiple animal species. Further optimiza-
tion of the human whole blood activity and PK profiles of our lead
hydantoin TACE inhibitors will be reported in future publications.
that hydrogen bonding accepting ability in the area very close to
the 3- or 4-position of the phenyl ring is beneficial for hWBA. Since
hydrogen bond accepting groups were tolerated the next step was
to determine if basic functionalities could be added to this portion
of the molecule. When basic heterocycles such as 37 and 38 were
N
O
O
N
O
HN
O
N
H
37
TACE K i = 0.62 nM
h WBA = 220 nM
Enzyme IC50 (nM)
MMP1
MMP3
MMP9
5200 MMP2 431
5800 MMP7 >40000
1010 MMP13 2920
ADAM10 22
Monkey PK (Na+ salt):
Dog PK (Na+ salt):
Rat PK (Na+ salt):
iv Dose (mg/kg) 1
AUC (uM.h) = 3.8
T1/2 (h) = 2.4
iv Dose (mg/kg) 0.5
AUC (uM.h) = 1.3
T1/2 (h) = 0.9
iv Dose (mg/kg) 3
AUC (uM.h) = 7.3
T1/2(h) = 2.2
Cl (L/h/kg) = 13
Cl (L/h/kg) = 19
Cl(L/h/kg) = 19
po Dose (mg/kg) = 3
AUC (uM.h) = 2.6
Tmax (h) = 1.2
F% = 23
po Dose (mg/kg) = 5
AUC (uM.h) = 1.1
Tmax (h) = 0.1
F% = 9
po Dose (mg/kg) = 10
AUC (uM.h) = 4.0
Tmax(h) =2 .2
F% = 15
Figure 2. Overall profile of compound 37.

V. M. Girijavallabhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7283–7287
7287
Rosner, K. E.; Shih, N. Y.; Siddiqui, M. A.; Guo, Z.; Orth, P.; Shah, H.; Sun, J.;
Umland, S.; Lundell, D. J.; Niu, X.; Kozlowski, J. A. Bioorg. Med. Chem. Lett. 2010,
20, 5286; For non-hydantoin inhibitors see: (b) Rosner, K. E.; Guo, Z.; Orth, P.;
Shipps, G. W.; 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, 1189;
(c) Li, D.; Popovici-Muller, J.; Caldwell, J.; Dai, C.; Belanger, D.; Girijavallabhan,
V. M.; Lavey, B. J.; Lee, J. F.; Liu, Z.; Mazzola, R.; Rizvi, R.; Rosner, K. E.; Shankar,
B. B.; Spitler, J.; Ting, P. C.; Vaccaro, H.; Yu, W.; Zhou, G.; Zhu, Z.; Niu, X.; Sun, J.;
Guo, Z.; Orth, P.; Chen, S.; Kozlowski, J. A.; Lundell, D. J.; Madison, V.;
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free medium (RPMI,
compound in a 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-glutamine, Pen-Strep, HEPES) and incubated with a
l
a
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Feltz, R. J.; Girijavallabhan, V. M.; Kim, S. H.; Kozlowski, J. A.; Lavey, B. J.; Li, D.;
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15. Attempts were made to make correlations between hWBA and protein binding
but no trends were apparent. It became clear through our studies that hWBA
optimization was empirical.