Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-α converting enzyme (TACE): Discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1′ substituents

Article abstract of DOI:10.1016/j.bmcl.2008.01.120

Potent and selective inhibitors of tumor necrosis factor-α converting enzyme (TACE) were discovered with several new heterocyclic P1′ groups in conjunction with cyclic β-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best o

Full text of DOI:10.1016/j.bmcl.2008.01.120

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1958–1962
Potent, selective, orally bioavailable inhibitors of tumor necrosis
factor-a converting enzyme (TACE): Discovery of indole,
benzofuran, imidazopyridine and pyrazolopyridine P10 substituents
Zhonghui Lu,* Gregory R. Ott,* Rajan Anand, Rui-Qin Liu, Maryanne B. Covington,
Krishna Vaddi, Mingxin Qian, Robert C. Newton, David D. Christ,
James Trzaskos and James J.-W. Duan
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 26 December 2007; revised 30 January 2008; accepted 30 January 2008
Available online 7 February 2008
Abstract—Potent and selective inhibitors of tumor necrosis factor-a converting enzyme (TACE) were discovered with several new
heterocyclic P10 groups in conjunction with cyclic b-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided
the best overall profile when combined with tetrahydropyran b-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed
IC50 value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-a of human whole blood. Com-
pound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F% > 90%) in
rat n-in-1 PK studies.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Tumor necrosis factor-a (TNF-a), a cytokine pro-
duced by activated macrophages and monocytes, is a
principal mediator of inflammatory response. In par-
ticular, TNF-a has been shown to be overexpressed
in the joints of rheumatoid arthritis patients.1 The
clinical success of anti-TNF-a biologics, such as
Enbrel, Remicade and Humira, has validated TNF-a
as a drug discovery target.2 As a result, many ap-
proaches to intersect the TNF-a signaling pathway
with orally active small molecules are being pursued.3
One such approach is through the inhibition of
TNF-a converting enzyme (TACE), which is responsi-
ble for the release TNF-a from cells.4
activity against the MMP family. Broad-based MMP
inhibitors were shown to have musculoskeletal side
effects in clinical trials.5 Recently, inhibitors with selec-
tivity for TACE against MMPs have been reported.6
Figure 1 shows three representative compounds from
our laboratory, c-lactamhydroxamic acid 1,7 tetrahy-
dropyran-b-aminohydroxamic acid 2,8 and pyrrolidine-
b-aminohydroxamic acid 3.9 The commonly shared
4-(2-methylquinolin-4-ylmethoxy)phenyl group was
designed and optimized to bind to the S10 pocket of
TACE, which was demonstrated to be the critical
O
H
TACE (ADAM-17) is a Zn-dependent metalloprotein-
ase belonging to a subclass of the metzincin superfamily.
Due to structure similarities between the active sites of
TACE and related matrix metalloproteinases (MMPs),
early TACE inhibitors were derived from MMP inhibi-
tors and consequently suffered from broad spectrum
N
N
HO
O
O
N
1
O
H
N
N
N
N
H
N
HO
O
O
HO
O
O
HN
HN
Keywords: TACE inhibitors; MMP inhibitors.
*
O
O
2
3
Corresponding authors. Tel.: +1 609 252 3178; fax: +1 609 252 6804
(Z.L.), tel.: +1 610 738 6861 (G.R.O.); e-mail addresses:
zhonghui.lu@bms.com; gott@cephalon.com
Figure 1. Representative TACE inhibitors from BMS.
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.120

Z. Lu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1958–1962
1959
determinant for TACE selectivity.7 In addition, this
group was also found to improve cellular activity and
pharmacokinetic profile.
CHO
+
a
O
O
NH
N
H
10
H3C
O
O
11
9
One of the concerns was the potential O-dealkylation
in vivo, which would generate phenols that have broad
MMP inhibitory activity. Second, although compounds
1–3 had excellent selectivity (>500-fold) against most of
the MMPs, they all showed some level of activity for
MMP-3, -7, -8, -12.8,9 In our efforts to address these
issues, we designed several [5,6] bicyclic hetereocycles
(Fig. 2) and evaluated them using tetrahydropyran-
and pyrrolidine-derived b-aminohydroxamic acid scaf-
folds. Because of the critical role of 2-methylquinoline
on selectivity, most of this work was focused on
2-substituted [5,6] bicyclic hetereocycles attached to
the benzamide at 1 or 3 position. The results from
2-substituted-1H-benzo[d]imidazole P10series (4) were
reported in a separate paper.10 This paper discloses the
preparation and activity of P10 analogs with indoles
(5), benzofurans (6), imidazo[1,2-a]pyridines (7), and
pyrazolo[1,5-a]pyridines (8).
BOC
N
c
O
b
+
HO
NH
O
NH2
O
13
12
BOC
BOC
N
H
N
O
N
HO
d
O
O
HN
NH
HN
NH
O
14
O
15
H
NH
O
N
HO
e
O
HN
NH
16
Scheme 1. Reagents: (a) Et3SiH, TFA, CH2Cl2 (78%); (b) LiOH, H2O,
THF (99%); (c) BOP, DIPEA, DMF (87%); (d) NH2OH, NaOMe,
MeOH (50%); (e) TFA, CH2Cl2 (100%).
Scheme 1 illustrates the synthesis of 2-substituted indole
P10 series. Reaction of methyl 4-formylbenzoate 9 with
2-methylindole 10 using triethylsilane and trifluoroacetic
acid in dichloromethane provided the benzyl-substituted
indole 11,11 which was hydrolyzed to acid 12. Com-
pound 12 was coupled with amine 139 using BOP re-
agent to yield amide 14. Treatment of 14 with
hydroxylamine and sodium methoxide in methanol
gave 15, which was deprotected with TFA to yield 16.
Compounds 17–19 were synthesized using a similar
sequence.
O
CO2CH3
a
b
O
O
O
21
20
O
CO2CH3
c
CO2H
O
+
O
NH2
O
22
O
24
23
Scheme 2 shows the synthesis of analogs of the benzofu-
ran P10 series. Ketone 20 was alkylated with methyl
4-bromomethylbenzoate using sodium hydride in THF
to provide 21. Treatment of 21 with boron tribromide
in dichloromethane resulted in selective demethylation
of the phenyl ether, formation of cyclic hemiketal and
dehydration in one pot to give the desired benzofuran
22. After hydrolysis of the ester, the resultant acid 23
was coupled with amine 248 using BOP reagent followed
by hydroxamic acid formation to yield compound 25.
Compounds 26–28 were synthesized following a similar
sequence.
O
H
N
c,d
HO
O
HN
O
O
25
Scheme 2. Reagents: (a) methyl 4-bromomethylbenzoate, NaH, THF
(76%); (b) BBr3, CH2Cl2(70%); (c) NaOH, H2O, MeOH (100%); (d)
BOP, DIPEA, DMF (90%); (e) NH2OH, NaOMe, MeOH (54%).
Br
O
O
N
d
a,b
c
N
Br
N
N
29
30
31
32
X
H
N
H
N
X
HO
n
HO
n
CO2Me
N
CO2H
O
O
HN
N
HN
Y
R
f
e
R
N
N
O
O
4
7
5 (Y=NH)
6 (Y=O)
N
33
N
34
H
X
H
X
N
N
HO
n
HO
n
N
Scheme 3. Reagents and conditions: (a) LDA, TMSCl, THF (79%);
(b) Br2, CH2Cl2 (97%); (c) 2-aminopyridine, EtOH, at reflux (16%); (d)
Br2, CH2Cl2 (83%); (e) 4-(methoxycarbonyl)benzylzinc bromide,
Pd(PPh3)4, THF (33%); (f) LiOH, H2O, THF (73%).
N
O
O
HN
HN
N
N
R
R
O
O
8
1) X=O, n=2
2) X=NR', n=1
The synthesis of imidazopyridine P10 acid started from
1-cyclopropylethanone 29 (Scheme 3). Treatment with
Figure 2. Tetrahydropyran and pyrrolidine-b-aminohydroxamic acid
scaffolds with [5,6] bicyclic heterocycle P10 substituents.

1960
Z. Lu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1958–1962
LDA followed by chlorotrimethylsilane provided a silyl
enol ether, which was reacted with bromine to provide
the bromide 30. Cyclocondensation of 30 with 2-amino-
pyridine in ethanol at reflux provided the desired imi-
dazopyridine 31 in 16% yield.12 Subsequent
bromination and palladium-catalyzed cross-coupling
with 4-(methoxycarbonyl)benzylzinc bromide yielded
the ester 33, which was hydrolyzed to the acid 34.
only about 73-fold. Introduction of 2-propynyl group
to the pyrrolidine nitrogen (compound 17) failed to
improve the selectivity against MMP-12 and led to
further loss of selectivity against MMP-3 and -7, even
though pTACE and WBA activities were maintained.
Replacing the pyrrolidine with a tetrahydropyran
(18) resulted in a slightly weaker inhibitor compared
to compound 16 (6 vs 2.2 nM). Changing the 2-indole
substituent from methyl to ethyl improved pTACE
potency 6-fold (18 vs 19), however, the selectivity
against MMP-12 was still not satisfactory. The 2-
methylbenzofuran analogs (25 and 26), while main-
taining good pTACE and WBA potency, resulted in
reduced selectivity against MMP-12. The bulky 2-iso-
propylbenzofuran derivatives (27 and 28) led to fur-
ther loss of WBA potency and failed to improve
selectivity against MMP-12.15 The potential reasons
for the loss in WBA activity for the benzofuran ana-
logs may be related to the increase in lipophilicity
leading to poor cell permeability. Recently described
scaffolds with increased lipophilicity have demon-
strated less favorable potency in the WBA.8,9 Further-
more, studies on the c-lactam scaffold (1) have
revealed that subtle changes to the P10 group can im-
pact WBA potency.7a
The synthesis of pyrazolopyridine P10 acid is outlined in
Scheme 4. Following a procedure reported by Potts, 1-
aminopyridinium iodide 35 was reacted with ethyl
1,1,1-trifluoro-2-butynoate 36 via [3 + 2] cycloaddition
followed by air oxidation to provide the pyrazolopyri-
dine 37 in 73% yield.13 Saponification and decarboxyl-
ation of 37 provided compound 38, which was
brominated to yield 39. After treatment with butyllith-
ium, the lithiated pyrazolopyridine intermediate was re-
acted with methyl 4-formylbenzoate to give an
intermediate alcohol that was reduced with triethylsilane
and trifluoroacetic acid to provide 40. Hydrolysis with
NaOH completed the synthesis of acid 41. Following
conditions shown in Schemes 1 and 2 acids 34 and 41
were coupled with b-aminoacid 24 and converted to
the hydroxamic acids. Other analogs containing differ-
ent substituents at 2-position of the imidazopyridine
and the pyrazolopyridine were synthesized following a
similar sequence.
Next, we turned our attention to imidazo[1,2-a]pyridine
and pyrazolo[1,5-a]pyridine P10 groups. From this point
on, SAR study was carried out using the tetrahydropy-
ran scaffold because it was found to have more desirable
oral absorption than the pyrrolidine scaffold. 2-Methy-
limidazo[1,2-a]pyridin-3-yl analog 42 displayed potent
activity in pTACE (1 nM) and WBA (122 nM). Further-
more, it had considerably improved MMP selectivity
compared to the indole analog (18) and benzofuran ana-
log (25). In fact, it was greater than 1000-fold selective
against all four MMPs. Replacing the 2-methyl substitu-
ent with isopropyl and cyclopropyl (43 and 44) resulted
in two compounds with an almost identical profile. Both
increased WBA potency to 74 nM and MMP-12 potency
2-fold. Interestingly, the trifluoromethyl analog 45 was
most selective against MMP-12 (>2000-fold), even
though its potency in WBA dropped by 2-fold compared
to 42. Unfortunately, these imidazo[1,2-a]pyridine ana-
logs suffered from poor oral bioavailability in rat. For
example, compound 45 had oral bioavailability of 10%
in a rat n-in-1 PK study. The low oral bioavailability ob-
served for 45 may, in part, be attributed to poor absorp-
tion. In vitro screening parameters predictive of oral
absorption (Caco-2) for 45 suggested that this may have
adversely impacted oral PK (Papp (A to
B) = 0.05 · 10ꢀ6 cm/s).
Compounds were evaluated in vitro using porcine
TACE (pTACE), as a result of its availability and
homology to human TACE.14 Selectivity profile was ini-
tially tested against MMP-2, 3, -7, and -12. Cellular sup-
pression of TNF-a was measured using human whole
blood (WBA) stimulated with lipopolysaccharide
(LPS). Pharmacokinetic studies were conducted using
cassette-dosing (n-in-1) administered intravenously and
orally to Sprague–Dawley rats.
The 2-methylindole group, when combined with a pyr-
rolidine core (compound 16, Table 1), gave very po-
tent activity in pTACE and WBA assays (2.2 and
52 nM, respectively). Compound 16 also had excellent
selectivity (600-fold or greater) against MMP-2, -3,
and -7. However, its selectivity against MMP-12 was
CF3
N
CO2Et
CF3
N
EtO2C
a
+
b,c
d
I-
NH2
N+
N
N
CF3
36
35
37
CO2Me
38
N
CO2H
CF3
N
For the pyrazolo[1,5-a]pyridine P10 analogs, 2-ethyl and
isopropyl derivatives (46 and 47) gave poor selectivity
against MMP-12 (Ki of 327 and 119 nM, respectively).
The t-butyl analog 48 attenuated the MMP-12 activity
to 726 nM. Finally, incorporation of a 2-trifluoromethyl
group (49) totally abolished MMP-12 activity. When 49
was tested in a panel of 11 MMPs, it was inactive in all
of the assays (Table 2). Compound 49 also maintained
good potency in the LPS–TNF-a whole blood assay
(171 nM, Table 1).
Br
e,f
g
N
CF3
CF3
N
N
N
39
40
41
Scheme 4. Reagents and conditions: (a) K2CO3, DMF, O2 (73%); (b)
LiOH, H2O, MeOH (100%); (c) HBr (aq), at reflux (70%); (d) Br2,
EtOH (91%); (e) Methyl 4-formylbenzoate, n-BuLi, THF, ꢀ78 ꢁC
(49%); (f) Et3SiH, TFA, CH2Cl2 (91%); (g) NaOH, H2O, MeOH
(100%).

Z. Lu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1958–1962
Table 1. In vitro profiles of the inhibitors with new heterocyclic P10 moieties
1961
O
O
O
X
H
N
H
N
H
N
H
N
N
HO
HO
HO
HO
N
O
HN
O
HN
O
HN
O
HN
Y
Y
N
N
R
R
R
R
O
O
O
O
A
B
C
D
Compounds 16, 17, 26, 27
Compounds 18, 19, 25, 28
Compounds 42-45
Compounds 46-49
Compound Scaffold
X
Y
R
pTACEa IC50 WBAb IC50 MMP-2
MMP-3
Ki (nM) Ki (nM) Ki (nM) Ki (nM)
MMP-7
MMP-12
(nM)
(nM)
16
17
18
19
25
26
27
28
42
43
44
45
46
47
48
49
A
A
B
NH
NH Me
2.2
1.0
6
52
76
>3333
2933
2970
852
1336
311
160
70
NCH2CꢁCH NH Me
—
—
—
NH
NH
—
—
—
—
—
—
—
—
—
NH Me
NH Et
164
112
168
220
1230
626
122
74
>3333
3300
3690
3060
1123
627
1527
2992
65
B
1.0
1.6
1.0
1.8
2.1
1.0
3.2
107
53
B
O
Me
Me
i-Pr
i-Pr
Me
i-Pr
>3333
1367
3311
1145
A
A
B
O
43
85
O
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
2719
766
>6368
811
O
10
C
C
C
C
D
D
D
D
—
—
—
—
—
—
—
—
>4501
>4501
>4501
>4501
3306
3305
>4501
>4501
>6368
>6368
>6368
>6368
>6368
2647
1021
580
540
3245
327
119
726
>6023
Cyclopropyl 1.0
74
CF3
Et
1.5
2.0
1.7
2.8
1.0
260
65
i-Pr
t-Bu
CF3
108
151
171
>6368
>6368
a pTACE IC50 and MMP Ki values are average of 2–6 determinations.
b Inhibition of TNF-a release in WBA was determined using three donors.
Table 2. Selectivity profile of inhibitor 49
Table 3. Rat n-in-1 pharmacokinetic parametersa
Enzyme
Ki (nM)
PK parameters
46
48
49
pTACE (IC50
MMP-1
MMP-2
)
1.0
Iv
Dose (mg/kg)
t1/2 (h)
1.0
14
1.0
0.7
1.0
3.4
>4946
>3333
>4501
>6368
>3058
>2128
>5346
>6023
>5025
>5290
>7088
Cl (L/h/kg)
Vss (L/kg)
AUC (nM h)
0.3
0.3
5559
0.7
0.3
0.6
1.0
MMP-3
MMP-7
2981
3584
MMP-8
MMP-9
Po
Dose (mg/kg)
t1/2 (h)
2.5
3.2
7228
52
2.5
2.1
3570
48
2.5
1.9
MMP-10
MMP-12
MMP-13
MMP-14
MMP-15
AUC (nM h)
F%
10,104
>90
a Determination of three for each dosing group, average value.
substitutents. Among them, the pyrazolopyridine P10
series showed the best overall profile. In particular,
inhibitor 49 proved to be potent for pTACE, selective
over a wide panel of MMPs, and potent in the suppres-
sion of LPS-induced TNF-a in human whole blood.
More importantly, 49 displayed excellent oral bioavail-
ability (F > 90%) in rat n-in-1 PK studies.
In contrast to the Caco-2 result for 45 containing the
isomeric imidazopyridine heterocycle, examples 46–49
containing the pyrazolopyridine heterocycle demon-
strated Caco-2 values consistent with oral absorption
(Papp (A to B): 46, 1.1 · 10ꢀ6, 48, 4.3 · 10ꢀ6 and 49,
1.8 · 10ꢀ6 cm/s). Compounds 46, 48 and 49 were exam-
ined in rat n-in-1 PK studies. The results are shown in
Table 3. Generally, these compounds were characterized
by low clearance (<1.0 L/h/kg), good oral bioavailability
(F > 48%) and high AUC (>3000 nM h, po). Inhibitor
49 stood out as having the best PK profile with oral bio-
availability of 90%.
Acknowledgments
We thank John Giannaras, Sherrill Nurnberg and Paul
Strzemienski for running in vitro assays, Bernice Brog-
don, Bing Lu, Hang Zheng and Jingtao Wu for assis-
tance in pharmacokinetic studies and Maria
Ribadeneira for Caco-2 assay. We also thank Dr. James
In summary, using b-amino hydroxamic acid scaffolds
several heterocycles were discovered to be excellent P10

1962
Z. Lu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1958–1962
Cherney, R. J.; Nelson, D. J.; Hardman, K. D.; Decicco,
C. P. Chem. Biol. 2003, 10, 215.
Sheppeck and Dr. Robert Cherney for reviewing the
draft.
8. Duan, J. J.-W.; Chen, L.; Lu, Z.; Xue, C.-B.; Liu, R.-Q.;
Covington, M. B.; Qian, M.; Wasserman, Z. R.; Vaddi,
K.; Christ, D. D.; Trzaskos, J. M.; Newton, R. C.;
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14. Details of the pTACE , MMPs, human whole blood
(WBA) assays as well as LPS-mouse efficacy model are
reported in previous publication, see: Xue, C.-B.; Voss, M.
E.; Nelson, D. J.; Duan, J. J.-W.; Cherney, R. J.;
Jacobson, I. C.; He, X.; Roderick, J.; Chen, L.; Corbett,
R. L.; Wang, L.; Meyer, D. T.; Kennedy, K.; DeGrado,
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R. R.; Decicco, C. P. J. Med. Chem. 2001, 44, 2636.
15. Attempts to gain insight via molecular modeling into the
origins of selectivity for MMP-12 for examples containing
the trifluoromethyl substituent provided no clear rationale
for the observed selectivity and potentially may be related
to subtle electrostatic interactions as increasing steric bulk
provided only marginal increases in selectivity.