Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-α converting enzyme inhibitors. Part 2: Lead optimization

Article abstract of DOI:10.1016/j.bmcl.2003.09.057

Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-{[4-(4- quinolinyloxymethyl)anilinyl]carbonyl}-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-α release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl] carbonyl}-5-piperidinecarboxamide] exhibited an IC₅₀ value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.

Full text of DOI:10.1016/j.bmcl.2003.09.057

Bioorganic & Medicinal ChemistryLetters 13 (2003) 4299–4304
Rational Design, Synthesis and Structure–Activity Relationships
of a Cyclic Succinate Series of TNF-ꢀ Converting Enzyme
Inhibitors. Part 2: Lead Optimization
Chu-Biao Xue,* Xiaohua He, John Roderick, Ronald L. Corbett, James J.-W. Duan,
Rui-Qin Liu, Maryanne B. Covington, Mingxin Qian, Maria D. Ribadeneira,
Krishna Vaddi, David D. Christ, Robert C. Newton, James M. Trzaskos,
Ronald L. Magolda, Ruth R. Wexler and Carl P. Decicco
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 27 May2003; revised 27 May2003; accepted 27 September 2003
Abstract—Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-{[4-(4-quinolinyloxymethyl)anilinyl]carbonyl}-1-cyclo-
hexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing
TACE inhibitors with potent activityin the inhibition of TNF- a release in the whole blood assay(WBA). The most potent analogue
IM491 [N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide] exhibited
an IC50 value of 20 nM in WBA with excellent selectivityover MMP-1, -2 and -9 and is orallybioavailable with an F value of 43%
in beagle dogs.
# 2003 Elsevier Ltd. All rights reserved.
Tumor necrosis factor-a (TNF-a)1 is a keyproin-
flammatorycytokine that plays a pivotal role in a number
of autoimmune diseases such as rheumatoid arthritis
(RA).2 Over-expression of TNF-a has been shown in
the joint of RA patients.3 The clinic success of anti-
TNF-a biologics, which neutralize TNF-a activityby
forming biologicallyinactive complex with the ctyo-
kine,4 has validated TNF-a as a target for the treatment
of RA and stimulated considerable interest in small
molecule TNF-a converting enzyme (TACE) inhibitors
recently.5 TACE6 is responsible for the processing of
inactive membrane-anchored proform of TNF-a to its
active soluble form. It is believed that inhibition of
TNF-a through inhibition of TACE mayrepresent a
new potential therapeutic target for the treatment of
RA.7
exemplified bycompound 1 (Fig. 1). Compound 1 is a
six-membered cyclic succinate derivative with 4-[(4-qui-
nolinyl)oxymethyl]aniline as a P10 residue and as a
racemic mixture, showed potent porcine TACE
(pTACE) activitywith an IC
of 8 nM and excellent
50
selectivityover MMP-1, -2, -9 and aggrecanase. Unfor-
tunately, compound 1 is ineffective in the inhibition of
TNF-a release in the cellular assay. In this communi-
cation, we report that optimization at the six-membered
carbocycle and the quinoline moiety led to the identifi-
cation of a new series of selective TACE inhibitors with
potent anti-TNF-a activityin the cellular assayas
represented by 4b (IM491, Fig. 1).
Synthesis
In the preceding communication,8 we described the
rational design of TACE inhibitors based on the Ciba-
Geigy’s sulfonamide CGS 27023A,9 which led to the
identification of a novel series of TACE inhibitors as
Compounds 2a–v were synthesized using the procedures
described in Scheme 1. Opticallypure (3 R,4S)-4-(tert-
butoxycarbonyl)-3-piperidinecarboxylic acid (5), which
was prepared as described in the literature,10 was reac-
ted with allyl chloroformate in a mixed solvent of water
and THF using N-methylmorpholine as a base to pro-
vide the N-allyloxycarbonyl intermediate 6 in 75%
yield. Alkylation of 6 with allyl bromide in the presence
*Corresponding author. Tel.: +1-302-283-7706; fax: +1-302-283-
7855; e-mail: cxue@incite.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.09.057

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C.-B. Xue et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4299–4304
Scheme 2. Reagents and conditions: (a) 4-[(2-methyl-4-quinoli-
nyl)methoxy]aniline, BOP, DIEA, DMF, 78%; (b) TFA, CH2Cl2,
100%; (c) an aldehyde, Na(OAc)3BH, DIEA, THF or 2-furoyl chlor-
ide, NMM, THF, H2O; (d) hydroxylamine hydrochloride, DIEA,
BOP, DMF.
Figure 1.
Compounds 3a–e were synthesized using the protocols
outlined in Scheme 2. Opticallypure (3 R,4S)-1,4-bis-
(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (11),
which was synthesized as described in the literature,10
was condensed with 4-[(2-methyl-4-quinolinyl)methoxy]
aniline11 using BOP to provide the anilide 12 in 78%
yield. Treatment of 12 with TFA removed the Boc and
tert-butyl groups. The final products 3a–e were obtained
byreductive amination of the resulting amine with an
aldehyde or by acylation with 2-furoyl chloride followed
bycoupling of the resulting carboxlyic acids with
hydroxylamine using BOP.
Compounds 4a–e were synthesized using the sequence
depicted in Scheme 3. Without protection of the sec-
ondarypiperidne amine, the enantiopure (2 S,3S)-3-
(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (14),
which was prepared as described in the literature,10 was
coupled with 4-[(2-methyl-4-quinolinyl)methoxy]aniline
using BOP to give the anilide 15 in 68% yield. Reduc-
tive amination of 15 with an aldehyde using
Na(OAc)3BH provided the tertiaryamine 16. Following
removal of the tert-butyl group using TFA, the resulting
carboxylic acid was converted to a hydroxamic acid as
described above.
Scheme 1. Reagents and conditions: (a) allyl chloroformate, NMM,
THF, H2O, 0 ꢀC, 75%; (b) allyl bromide, K2CO3, acetone, reflux,
85%; (c) TFA, CH2Cl2, 100%; (d) an aniline derivative, BOP, DIEA,
DMF; (e) tetrakis(triphenylphosphine)palladium, pyrrolidine, THF;
(f) aldehyde, Na(OAc)3BH, DIEA, THF or chloroformate, NMM,
THF, H2O or acid chloride, NMM, THF, H2O or sulfonyl chloride,
NMM, THF, H2O or isocyanate, DIEA, THF; (g) hydroxylamine
hydrochloride, BOP, DIEA, DMF.
Results and Discussion
12
Since compound 1 had high affinityfor pTACE
(IC50=8 nM), we reasoned that the poor inhibition of
TNF-a release in WBA (IC50>50 mM) might be caused
by the lipophilicity of the cyclohexyl ring which could
make the molecule highlyprotein-bound. Thus the
cyclohexyl ring in 1 was replaced with a piperidine ring
to provide a new series of 3,4-piperidinedicarboxamide
derivatives (Table 1). With a cyclopropanecarbonyl
group on the piperidine nitrogen, analogue 2a showed
4-fold improvement in pTACE activityrelative to 1 with
maintenance of selectivityprofile over MMP-1, -2 and
-9. More importantly, this modification significantly
boosted the cellular potency: 2a displayed an IC50 value
of 0.71 mM in WBA, which is >70-fold improvement
of K2CO3 provided the diester 7 which was treated with
TFA to give the carboxylic acid 8. Coupling of the
carboxylic acid 8 with an aniline derivative using BOP
gave rise to the anilide product 9. After removal of the
allyloxycarbonyl and allyl groups by treatment with
pyrrolidine/tetrakis(triphenylphosphine)palladium, the
resulting amine was subjected to a reductive amination,
acylation, sulfonylation, reaction with a chloroformate
or an isocyanate to give the intermediate 10. Conversion
of the carboxylic acid to a hydroxamic acid by coupling
with hydroxylamine hydrochloride using BOP afforded
the final products 2a–v.

C.-B. Xue et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4299–4304
4301
pTACE versus MMP-9. Unfortunately, analogue 2h had
a low water solubility(0.01 mg/mL), low Caco-2 perme-
ability( Papp=0.1ꢁ10ꢂ6 cm/s) and low oral bioavail-
ability(5%) when dosed to beagle dogs ( Table 2).
To improve the water solubility, Caco-2 permeability
and oral bioavailabilityof 2h, a varietyof substituents
on the piperidine nitrogen were examined while keeping
the 4-[(2-methyl-4-quinolinyl)methoxy]anilinyl at P10
constant (Table 2). The N-acyl analogues 2i–k, urea
analogue 2l and carbamate analogues 2o–s all showed
WBA potencycomparable to 2h but no improvement in
permeability, solubility and oral biavailability over 2h,
whereas a slight loss in cellular potencywas observed
with the sulfonamide analogues 2m–n and the secondary
and tertiaryamino analogues 2t–v. Comparison in
water solubilityof analogues 2t–v with other analogues
in Table 2 indicates that the basic piperidine nitrogen in
the molecule in 2t–v significantlyimproved water
solubility( >10 mg/mL), which prompted us to explore
new analogues bearing a basic piperidine nitrogen (vide
infra).
Scheme 3. Reagents and conditions: (a) 4-[(2-methyl-4-quinoli-
nyl)methoxy]aniline, BOP, DIEA, DMF, 68%; (b) aldehyde,
Na(OAc)3BH, DIEA, THF; (c) TFA, CH2Cl2; (d) hydroxylamine
hydrochloride, BOP, DIEA, DMF.
over compound 1. To optimize the P10 residue, several
quinoline-containing P10 groups were investigated using
the piperidine template of 2a. While exchanging the
positions of the oxygen and methylene between the
quinoline and aniline in 2a basicallymaintained the
potencyand selectivityprofile ( 2b), removal of the
methylene residue at that position resulted in complete
loss in pTACE and cellular activityas seen in 2c, sug-
gesting the importance of the methylene for the orien-
tation of the quinoline residue in the S10 pocket.13
Comparisons in pTACE and WBA potencybetween 2d
and 2e and between 2f and 2g indicate that substitution
at the 7-position with trifluoromethyl or at the 2-posi-
tion with methyl on the quinoline is detrimental to
pTACE and cellular activities. However, exchanging the
positions of the oxygen and methylene between the
quinoline and aniline in 2g afforded a potent analogue
2h, which exhibited IC50 values of 66 picomolar and 170
nM in pTACE and whole blood assays, respectively.
Although analogue 2h displayed a submicromolar
potencyfor MMP-9, it is still >7000-fold selective for
We next carried out SAR studies bymoving the piper-
idine nitrogen one atom awayfrom the hydroxamic acid
in 2h to provide a new series of 4,5-piperidinedicarbox-
amide derivatives (Table 3). In contrast to the 3,4-
piperidinedicarboxamide series in which the 2-furoyl
analogue 2h is much more potent than analogues 2t–v
with a basic piperidine nitrogen (Table 2), analogues
3b–e with a basic piperidine nitrogen in this series
exhibited better WBA potencythan the 2-furoyl analo-
gue 3a (Table 3). Of particular note in this series is that
the N-methyl analogue 3c is verypotent in the inhibi-
tion of TNF-a release, with an IC50 value of 100 nM in
the cellular assay. Despite its good water solubility, 3c
showed low Caco-2 permeabilityand low oral bioavail-
ability(9%) when dosed to beagle dogs. Attempts to
improve the Caco-2 permeabilityand oral bioavail-
abilitybyincreasing the size of the substituent on the
piperidine nitrogen resulted in a slight loss in WBA
potency as seen in the cyclopropylmethyl and 2-thiazo-
lemethyl analogues 3d and 3e.
Table 1. (3R,4S)-N3-Hydroxy-3,4-piperidinedicarboxamide derivatives with different P10 residuesaꢂc
Compd
R1
R2
PTACE
IC50, nM
WBA
IC50, mM Ki, nM
MMP-1 MMP-2 MMP-9
Ki, nM
Ki, nM
1
8.0
2.0
1.0
>50
0.71
1.3
>50
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
1011
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
465
2a
2b
2c
2d
2e
2f
2g
2h
4-[(4-Quinolinyl)oxymethyl]phenyl
4-[(4-Quinolinyl)methoxy]phenyl
4-[(4-Quinolinyl)oxy]phenyl
Cyclopropanecarbonyl
Cyclopropanecarbonyl
Cyclopropanecarbonyl >1000
4-[(4-Quinolinyl)oxymethyl]phenyl
4-[(7-Trifluoromethyl-4-Quinolinyl)oxymethyl]phenyl
4-[(4-Quinolinyl)oxymethyl]phenyl
Acetyl
Acetyl
2-Furoyl
2-Furoyl
2-Furoyl
1.0
3.2
0.80
3.0
0.56
2.6
0.70
3.4
4-[(2-Methyl-4-Quinolinyl)oxymethyl]phenyl
4-[(2-Methyl-4-Quinolinyl)methoxy]phenyl
0.066
0.17
aSee ref 12 for pTACE, WBA and MMP assayprotocols.
bpTACE IC50 and MMP Ki values are from single determination.
cInhibition of TNF-a release in whole blood assay(WBA) was determined with three donors.

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C.-B. Xue et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4299–4304
Table 2. (3R,4S)-N3-Hydroxy-3,4-piperidinedicarboxamide derivatives with 4-[(2-methyl-4-quinolinyl)methoxy]anilide at P10aꢂc
Compd
R
PTACE
IC50, nM
WBA
IC50, mM
MMP-1
Ki, nM
MMP-2
Ki, nM
MMP-9
Ki, nM
Caco-2 Papp
(ꢁ10ꢂ6 cm/s)
Solubility
mg/mL
Dog PK
F%
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2-Furoyl
Cyclopropanecarbonyl
Butyryl
2-Methylpropionyl
tert-Butylaminocarbonyl
Methanesulfonyl
1-Methyl-4-imidazolesulfonyl
Methoxycarbonyl
Isopropyloxycarbonyl
Cyclopropyloxycarbonyl
2-Thiazolemethoxycarbonyl
4-Thiazolemethoxycarbonyl
H
0.066
0.45
0.26
0.22
0.41
0.48
0.31
0.28
0.44
0.83
<0.3
<0.3
1.5
0.17
0.39
0.33
0.27
0.56
1.36
1.5
0.57
0.21
0.70
0.45
0.53
4.3
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
1011
2454
>3333
>3333
>3333
656
1002
1111
771
642
1537
476
>3333
>3333
>3333
465
1656
>2128
>2128
>2128
306
0.1
0.2
0.01
0.05
5
8
0.3
0.7
0.2
0.03
<0.01
<0.01
9
5
7
366
767
252
209
768
296
0.2
0.1
<0.01
<0.01
8
3
>2128
>2128
>2128
>10
>10
>10
2u
2v
Isopropyl
Cyclobutyl
1.2
1.6
1.2
1.1
apTACE IC50 and MMP Ki values are from single determination.
bInhibition of TNF-a release in whole blood assay(WBA) was determined with three donors.
cOral bioavailability( F%) from dog pharmacokinetics studies.
Table 3. (4S,5S)-N4-Hydroxy-4,5-piperidinedicarboxamide derivatives with 4-[(2-methyl-4-quinolinyl)methoxy]anilide at P10aꢂc
Compd
R
PTACE
IC50, nM
WBA
IC50, mM
MMP-1
Ki, nM
MMP-2
Ki, nM
MMP-9
Ki, nM
Caco-2 Papp
(ꢁ10ꢂ6 cm/s)
Solubility
mg/mL
Dog PK
F%
3a
3b
3c
3d
3e
2-Furoyl
H
Me
<0.3
3.0
5.0
1.0
0.80
1.3
>4949
>4949
>4949
>4949
>4949
>3333
>3333
>3333
>3333
>3333
>2128
>2128
>2128
>2128
>2128
0.2
<0.1
>10
>10
0.53
0.10
0.30
0.56
0.1
9
Cyclopropylmethyl
2-Thiazolemethyl
>10
apTACE IC50 and MMP Ki values are from single determination.
bInhibition of TNF-a release in whole blood assay(WBA) was determined with three donors.
cOral bioavailability( F%) from dog pharmacokinetics studies.
To further improve the cellular potencyand oral bio-
availability, SAR studies were next conducted by moving
the piperidine nitrogen next to the P10 residue to
provide a new series of 5,6-piperidinedicarboxamide
derivatives (Table 4). With no substitution and a methyl
substituent on the piperidine nitrogen, analogues 4a and
4b (IM491) showed 4- and 5-fold improvement over the
4,5-piperidinedicarboxamide counterparts 3b and 3c,
respectively, in WBA potency. IM491 is the most potent
TACE inhibitor identified so far in the inhibition of
TNF-a release from cells, with an IC50 value of 20 nM
in the whole blood assay. Accompanied by their excellent
WBA potencywere the good water solubility( >10 mg/
mL), excellent selectivityover MMP-1, -2, and -9 and
the decent Caco-2 permeabilityof these two analogues,
with Papp values of 2.2ꢁ10ꢂ6 and 2.1ꢁ10ꢂ6 cm/s for 4a
and IM491, respectively. The improved Caco-2 perme-
abilityof IM491 over 3c probablycan be explained by
the less basicityand more steric hindrance of the piper-
idine nitrogen in IM491 compared to 3c as the piper-
idine nitrogen is at a position a to the carboxamide in
IM491 but b to the carboxamide in 3c. In parallel to
their good permeability, analogues 4a and IM491
exhibited good oral bioavailabilityin beagle dogs, with
F values of 24% and 43% for 4a and IM491, respectively.
In addition to its good oral absorption, the favorable oral
bioavailabilityof IM491 mayalso be contributed from its
low clearance (0.6 L/h/kg). The lower oral bioavailability

C.-B. Xue et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4299–4304
4303
Table 4. (5S,6S)-N5-Hydroxy-5,6-piperidinedicarboxamide derivatives with 4-[(2-methyl-4-quinolinyl)methoxy]anilide at P10aꢂc
Compd
R
PTACE
IC50, nM
WBA
IC50, mM
MMP-1
Ki, nM
MMP-2
Ki, nM
MMP-9
Ki, nM
Caco-2 Papp
(ꢁ10ꢂ6 cm/s)
Solubility
mg/mL
Dog PK
F%
4a
4b (IM491)
4c
4d
4e
H
Me
1.0
6.2
8.0
1.0
1.0
0.12
0.020
0.10
0.40
1.4
>4949
>4949
>4949
>4949
>4949
>3333
>3333
>3333
>3333
>3333
>2128
>2128
>2128
>2128
>2128
2.2
2.1
>10
>10
>10
24
43
Et
Cyclopropylmethyl
2-Thiazolemethyl
apTACE IC50 and MMP Ki values are from single determination.
bInhibition of TNF-a release in whole blood assay(WBA) was determined with three donors.
cOral bioavailability( F%) from dog pharmacokinetics studies.
of 4a relative to IM491 is probablycaused byits relatively
high clearance (1.2 L/h/kg).
1996, 7, 93. (b) Eigler, A.; Sinha, B.; Hartmann, G.; Endres, S.
Immunol. Today 1997, 18, 487. (c) Newton, R.; Decicco, C. J.
Med. Chem. 1999, 42, 2295.
3. Feldmann, M.; Brennan, F.; Elliott, M.; Katsikis, E.;
Maini, R. Circ. Shock 1994, 43, 179.
A more considerable effect on WBA potencywas
observed in the 5,6-piperidinedicarboxamide series
(Table 4) compared with 4,5-piperidinedicarboxamide
series (Table 3) bythe increase in size of the substituent
on the piperidine nitrogen. Replacement of the methyl
group on the piperidine nitrogen in IM491 with ethyl
(4c), cyclopropylmethyl (4d) and 2-thiazolemethyl (4e)
resulted in 5-, 20- and 70-fold loss in cellular activity.
4. (a) Elliott, M.; Maini, R.; Feldmann, M.; Kalden, J.;
Antoni, C.; Smolen, J.; Leeb, B.; Breedveld, F.; Macfarlane,
J.; Bijl, H.; Woody, J. Lancet 1994, 344, 1105. (b) Elliott, M.;
Maini, R.; Feldmann, M.; Long-Fox, A.; Charles, P.; Bijl, H.;
Woody, J. Lancet 1994, 344, 1125. (c) Van Dullemen, H.; Van
Deventer, S.; Hommes, D.; Bijl, H.; Jansen, J.; Tytgat, G.;
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Baumgartner, S.; Schiff, M.; Tindall, E.; Fleischmann, R.;
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K.; Widmer, M.; Blosch, C. N. Engl. J. Med. 1997, 337, 141.
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man, Z.; Liu, R.-Q.; Jaffee, B.; Covington, M.; Qian, M.;
Trzaskos, J.; Newton, R.; Magolda, R.; Wexler, R.; Decicco,
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J.; Cowan, D.; Gaul, M.; Glennon, K.; Lambert, M.; Leesnit-
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In summary, to improve the cellular activity of the lead
TACE compound 1, modifications were carried out at
the cyclohexyl ring and the quinoline P10 residue.
Replacement of a methylene residue of the cyclohexyl
ring with a nitrogen at three different positions provided
a new series of piperidinedicarboxamide analogues which
significantlyimproved the WBA potenc.y With 4-[(2-
methyl-4-quinolinyl)methoxy]anilinyl at the P10 position,
the 5,6-piperidinedicarboxamide analogue IM491 bearing
a methyl group on the piperidine nitrogen was identified
as the most potent TACE inhibitor in the inhibition of
TNF-a release, with an IC50 value of 20 nM in the cellular
assay. IM491 also showed excellent selectivity over MMP-
1, -2 and -9, decent Caco-2 permeability, excellent water
solubilityand good oral bioavailabilityin beagle dogs.
Acknowledgements
We thank John Giannaras, Sherrill A. Nurnberg, Dian-
na L. Blessington, Persymphonie B. Miller, Theresa M.
Dimeo, Robert J. Collins, TracyL. Taylor and Paul J.
Strzemienski for performing in vitro and in vivo assays.
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