Identification of novel TACE inhibitors compatible with topical application

Article abstract of DOI:10.1016/j.bmcl.2017.02.035

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.

Full text of DOI:10.1016/j.bmcl.2017.02.035

Accepted Manuscript
Identification of novel TACE inhibitors compatible with topical application
Gilles Ouvry, Yaël Berton, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire
Bouix-Peter, Karine Bouquet, Marilyne Bourotte, Sandrine Chambon,
Catherine Comino, Benoît Deprez, Denis Duvert, Gwenaëlle Duvert, Feriel
Hacini-Rachinel, Craig S. Harris, Anne-Pascale Luzy, Arnaud Mathieu, Corinne
Millois, Jonathan Pascau, Artur Pinto, Gaëlle Polge, Arnaud Reitz, Kevin
Reversé, Carine Rosignoli, Nathalie Taquet, Laurent F. Hennequin
PII:
S0960-894X(17)30169-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.02.035
BMCL 24707
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 January 2017
15 February 2017
16 February 2017
Please cite this article as: Ouvry, G., Berton, Y., Bhurruth-Alcor, Y., Bonnary, L., Bouix-Peter, C., Bouquet, K.,
Bourotte, M., Chambon, S., Comino, C., Deprez, B., Duvert, D., Duvert, G., Hacini-Rachinel, F., Harris, C.S., Luzy,
A-P., Mathieu, A., Millois, C., Pascau, J., Pinto, A., Polge, G., Reitz, A., Reversé, K., Rosignoli, C., Taquet, N.,
Hennequin, L.F., Identification of novel TACE inhibitors compatible with topical application, Bioorganic &
Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.02.035
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Bioorganic & Medicinal Chemistry Letters
Identification of novel TACE inhibitors compatible with topical application
Gilles Ouvrya, Yaël Bertona, Yushma Bhurruth-Alcora, Laetitia Bonnarya, Claire Bouix-Petera, Karine
Bouqueta, Marilyne Bourotteb, Sandrine Chambona, Catherine Cominoa, Benoît Deprezb, Denis Duverta,
Gwenaëlle Duverta, Feriel Hacini-Rachinela, Craig S. Harrisa, Anne-Pascale Luzya, Arnaud Mathieub,
Corinne Milloisa, Jonathan Pascaua, Artur Pintob, Gaëlle Polgea, Arnaud Reitza, Kevin Reverséa, Carine
Rosignolia, Nathalie Taqueta and Laurent F. Hennequina.
aNestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410, Biot, France
bUniv. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the
treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE
or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis,
without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE
inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are
presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal
cellular activity of this series is discussed in the context of previously published results.
Keywords:
Keyword_1 TACE
Keyword_2 Hydroxamic acids
Keyword_3 Psoriasis
2009 Elsevier Ltd. All rights reserved.
Keyword_4 Topical application
Keyword_5 Enzyme-cell drop-off
———
 Corresponding author. Tel.: +33(0)-492383062; e-mail: gilles.ouvry@galderma.com

The advent of antibodies targeting the Tumor Necrosis Factor
α signalling has revolutionized our approach to psoriasis
treatment.1,2,3 Targeting this key pathway on a local level could
potentially be a way to treat mild psoriasis with a topical
compound. In this setting, the Tumor Necrosis Factor α
Converting Enzyme (TACE or ADAM17) stands out as a
druggable target for such an approach.4 Recent studies have also
suggested that inhibition of the TACE could also potentially
benefit other acne patients,5 highlighting this as a key target for
dermatology.
Coupling of the amine to the known chlorosulfonyl groups
followed by a saponification, when the starting material was an
ester, yielded the fully functionalized acid. Conversion of the
acid to the hydroxamate was done using different conditions: (1)
A one step procedure using in situ activation of the acid with
isobutylchloroformate and hydroxylamine; (2) synthesis of the
THP-protected hydroxamate using an in situ pentafluoroester
activation, followed by cleavage of the protecting group; (3)
synthesis and isolation of the pentafluoroester, followed by
synthesis of the hydroxamate.12 Amide linked compounds (10, 11
and 18) were synthesized using a similar approach.
TACE inhibitors have been intensely studied in the past and
were thought to have great potential in treating auto-immune
diseases like rheumatoid arthritis.6 Unfortunately, these inhibitors
have not been able to reach the market yet. This disappointing
result has often been linked to a lack of efficacy, poor
pharmacokinetics and/or toxicity issues potentially linked to a
lack of selectivity vs other matrix metalloproteinases (MMP).
The advantage of modulating TACE only locally would be to
limit systemic toxicity and potentially mitigate the risks
associated with previous programs.
Synthesis of compounds 20-27 started form the corresponding
hydroxyproline. 10,11 Scheme 2 depicts the synthesis of analog 24.
The thioether bond was synthesized using the tosylate of the
hydroxyproline. Oxidation using mCPBA followed by phenol
alkylation with the available quinoline chloride derivative
afforded ester 7. Saponification, followed by pentafluoroester
synthesis yielded the activated ester as the penultimate
intermediate. Reaction with hydroxylamine afforded the desired
compound.
Figure 1 highlights two of the most studied TACE inhibitors,
Apratastat (1) and DPC333 (2).7,8
Figure 1. Apratastat (1), DPC-333 (2) and representative structure from the
first generation of TACE inhibitors developed at Galderma (3)
Scheme 2. Synthesis of proline-based inhibitor 24: (i) TsCl, pyridine (52%);
(ii) p-hydroxythiophenol, Zn, K2CO3, acetone (70%); (iii) mCPBA, DCM
(94%); (iv) 4-(chloromethyl)-2-methyl-quinoline, K2CO3, KI, acetone (43%);
(v) LiOH.H2O, methanol (84%); (vi) N-(3-Dimethylaminopropyl)-N′-
ethylcarbodiimide hydrochloride, Et3N, pentafluorophenol, DCM (33%); (vii)
NH2OH in H2O, acetonitrile (15%)
Researchers at Galderma have identified a first generation of
TACE inhibitors (Figure 1; 3 is a representative compound from
this series) which has now reached the clinic.9 In order to secure
this area of interest, a back-up program was started with the aim
of identifying structurally distinct inhibitors.
Compounds were evaluated in a standard TACE enzymatic
assay.13 Activities of the different analogs are displayed in Table
1. The first striking observation is that the quinoline group
routinely shows activity whereas the alkyne does not (8 vs 9; 16
vs 17; 24 vs 25). At this stage, we decided to focus on the
quinoline group even though the impact of such group on
solubility and skin penetration would have to be carefully
assessed.
A quick survey of the literature highlighted the importance of
either a methyl quinoline group (as in DPC-33; 2) or an alkyne
group (as in Apratastat; 1) in the S1’ pocket of the enzyme to
ensure good potency and selectivity.6 Starting from these two
handles, we decided to broadly explore novel cyclic linkers to the
hydroxamic Zn binding group.
Syntheses of the compounds described in this manuscript were
relatively straightforward starting from the corresponding amino
acid or ester.10,11 Scheme 1 depicts the general strategy.
Comparing compounds 8/10 and 16/18 showed a preference
for the sulfonamide linker. 5, 6 and 7-membered rings were
tolerated (apart for acetyldiazepane 19) and so was incorporation
of heteroatoms (14 and 16).
The different proline-based isomers displayed disappointing
potency and were not explored any further. Instead pyrrolidine,
piperidine and piperazine were chosen as starting point for
further optimization.
Scheme 1. General synthetic approach to compounds described in this
manuscript:
(i)
Phenoxychlorosulfonyl
derivative,
triethylamine,
dioxane/water (2/1); (ii) NaOH, THF/water (5/1) 50° C; (iii) N-
methylmorpholine, isobutyl chloroformate, NH2OH.HCl, DMF; (iv)
EDCI.HCl,
yl)hydroxylamine, DCM; (v) TFA, DCM, 50° C; (vi) N-(3-
Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, Et3N,
pentafluorophenol, DCM; (vii) NH2OH in H2O, acetonitrile
Et3N,
pentafluorophenol,
O-(tetrahydro-2H-pyran-2-

Table 1. Cyclic linker exploration
b
TACE enz
(nM)a
clogD7.4
/LipEc
Cmpd
R
A
TACE
enz
b
Phenyl
substituent
clogD7.4
/LipEc
H
-
-
-
-
-
-
210
35
16
35
42
60
40
14
30
2.2/4.5
2.5/5
8
Compound
Core
(nM)a
Methyl
28a
28b
28c
28d
12
Ethyl
2.6/5.2
3.3/4.2
3.6/3.8
2.3/4.9
2.6/4.8
1.4/6.4
1.7/5.8
1
3
-
-
-
4
6
0.8/7.6
2.3/5.9
2.2/4.5
0.9/-
Isobutyl
-
CH2Phenyl
A
B
A
B
210
-
-
-
-
8
CH2
-
29a
16
>10000
6500
>10000
9
2.3/2.9
1.2/-
10
11
NAc
29b
a See supplementary material for assay description. Geomean of at least 2
determinations13
b Calculated using ADMET predictor
A
60
2.3/4.9
12
c LipE: Lipophilic efficiency is determined by pIC50-clogD7.4
Surprisingly, the effect of the added methyl group in the
pyrrolidine scaffold did not transfer to the piperidine scaffold
(29a vs 12) and was even slightly detrimental on the piperazine
scaffold.
A
84
3.0/4.1
13
A
A
180
71
1.8/4.9
1.9/5.3
14
15
At this stage, we had reached similarly high potencies on the
enzymatic assay with 28b and 16 (respectively 16 and 14 nM).
However, these compounds display significantly different logD
(2.5 vs 1.4) and LipE values (5.2 vs 6.4). Considering its high
LipE value, in addition to synthetic aspects, we found judicious
to explore the chemical space around piperazine 16.
A
B
14
1.4/6.4
0.3/5.5
16
17
1500
Scheme 3 depicts the synthesis of piperazine analog 31g as a
representative procedure for the synthesis of all the other N1-
modified piperazine analogs.10,11 Sulfonamide formation occurred
smoothly on the distal nitrogen using the general conditions
described earlier. Esterification followed by tert-butyl amide
synthesis afforded fully functionalized intermediate 30.
Saponification followed by a one-step hydroxylamine formation
gave the desired compound 31g.
A
A
760
200
1.5/4.6
1.5/5.2
18
19
A
B
A
B
A
B
A
B
>10000
>10000
>10000
>10000
350
1.7/-
0.4/-
20
21
22
23
24
25
26
27
1.7/-
0.4/-
1.7/4.8
0.4/-
>10000
3600
1.7/3.7
0.4/-
>10000
Scheme 3. Synthesis of piperidine-based inhibitor 31g: (i) 4-((2-
methylquinolin-4-yl)methoxy)benzenesulfonyl chloride, triethylamine,
dioxane/water (2/1) (84%); (ii) SOCl2, methanol (98%); (iii) 2,2-
dimethylpropanoyl chloride, Et3N, DCM (98%); (iv) LiOH.H2O, THF/H2O
(4/1) (87%); (v) N-methylmorpholine, isobutyl chloroformate, NH2OH.HCl,
DMF (17%)
a See supplementary material for assay description. Geomean of at least 2
determinations13
b Calculated using ADMET predictor
c LipE: Lipophilic efficiency is determined by pIC50-clogD7.4
A first exploration was made around the alpha position of the
hydroxamate (Table 2). Compounds were synthesized using the
general approach outlined in Scheme 1.10,11 Simple methylation
of the pyrrolidine scaffold provided a nice boost in potency
(28a). Moving to the ethyl was also overall beneficial (28b).
However, bulkier groups did not bring any notable advantage
(28c and 28d).
Table 3 highlights some of the substituents that were explored on
the N1-nitrogen, alpha to the hydroxamate.
Amide exploration highlighted that short aliphatic groups (31a,
31b, 31e), small cycloalkyl (31c, 31d), and even phenyl (31f) all
maintained good levels of potency. Sulfonamides (31i) and
carbamates (31h) were both surveyed and also displayed good
Table 2. α-alkylation exploration

potency. Finally, alkyl groups were rapidly scanned but showed
disappointing activity (31j, 31k, 31l).
Table 3. Piperazine exploration
31g
TACE enz IC50 (nM)a
12
>10/>10/>10/0.93
>10/>10
1.3
MMP1/MMP3/MMP9/MMP12 IC50 (µM)b
ADAM9/ADAM10 IC50 (µM)b
Cell assay (KHN) IC50 (µM)a
Fu (Hu)b
3%
TACE enz
(nM)a
Human
Cmpd
R
clogD7.4c /LipEd
Microsomesb
Human hepatocytes Clint
14
(µL/min/1e6 cells)b
Human keratinocytes T1/2 (hrs)b
>24
20
14
23
92
1.4/6.4
1.6/6.0
16
Aqueous Solubility (µM)c
Solubility in PG/EtOH96 (3/7) (mM)
Photo-irritancy factorb
100
31a
>55
1
26
13
91
88
1.9/5.7
1.9/6.0
31b
31c
a See supplementary material for assay description. Geomean of at least 2
determinations13
b See supplementary material for assay description.13
c Contains 1% DMSO
19
23
83
64
2.1/5.6
2.3/4.3
31d
31e
In order to understand this micromolar cellular activity, a series
of compounds from this manuscript were tested in the cell assay.
It turned out that apart from Apratastat (1) and compound 3,
representing Galderma’s first generation of inhibitors, none of
the compounds showed submicromolar potency in keratinocytes,
all the while showing good potency on the isolated enzyme assay
(Table 5).
16
12
85
47
2.5/5.3
2.3/5.6
31f
31g
40
29
100
88
1.9/5.5
1.8/5.7
31h
31i
Table 5. Keratinocyte cellular assay
Aqueous solubility
Compound
TACE enz (nM)a
KHN (µM)a
e
(µM)b,c
110
160
150
-
1.5/5.5
1.8/5.0
2.4/4.4
31j
31k
31l
80
4
6
0.12
0.06
>10
>10
>10
9.1
90
1
3
54
d
-
a See supplementary material for assay description. Geomean of at least 2
d
determinations13
210
60
84
14
350
35
13
-
8
b Stability in Human microsomes: % parent compound remaining after 15min
of incubation. See supplementary material for assay description.13
c Calculated using ADMET predictor
<1
12
13
16
24
28a
31c
d
-
61
d LipE: Lipophilic efficiency is determined by pIC50-clogD7.4
e Not tested
d
>10
>10
3.1
-
41
58
20
Out of all these, only compounds 31e, 31g and 31l showed
reasonable microsomal instability. This was sought after by the
project team as it would favour a locally acting compound with
limited systemic exposure after topical application. With the
highest LipE of the three, 31g was selected for further profiling
(Table 4).13
12
150
1.3
>10
31g
31l
d
-
a See supplementary material for assay description. Geomean of at least 2
determinations13
b See supplementary material for assay description.13
c Contains 1% DMSO
d Not tested
Compound 31g was potent in the enzymatic assay and selective
vs an in-house panel of MMPs and ADAMs. The compound
displayed properties compatible with topical administration: the
metabolic instability detected in microsomes was confirmed in
human hepatocytes; the compound was stable in human
keratinocytes with a half-life of more than 24 hours (this ensured
that the compound would not be metabolized in the skin);
reasonable aqueous solubility and good Propylene
Glycol/Ethanol (PG/EtOH) solubility highlighted the potential
for this series in different formulations; the compound was also
found to be negative in our phototoxicity assay.14 Overall,
compound 31g presented most of the characteristics we were
looking to find for a topical lead compound. Unfortunately,
cellular activity measured in keratinocytes was suboptimal.
TACE activity has been shown to be different depending on
the cell type.15 Figure 2 displays the potency of compounds from
different internal series optimized at Galderma in human
keratinocytes (KHN) and in human peripheral blood
mononuclear cells (hPBMC). The good correlation between the 2
assays over a good spread of IC50 suggested that the KHN model
was well suited to assess cellular potency of compounds.
Table 4. Property Scoring Card for 31g

Although not explicitly stated in the publications mentioned
above, the reasons for the non-correlation between isolated
TACE enzyme assays and cell-based assays could be multiple:

Cell permeability has often been a culprit for lack of
cellular activity,17 however it is not clear whether TACE
is an intracellular or extracellular target. 18

Poor solubility in the assay medium could impact results.
Aqueous solubility of some of the compounds is shown
in Table 5 and although the solubilities are higher than
the highest concentration tested in the assay for the most
part, we cannot rule out the possibility of precipitation in
some cases.

Barlaam et al mentioned the possible impact of an
entropic effect due to the colocalization of TACE and its
substrate.19 Residence time and tight binding could thus
be a key factor for these inhibitors.20
Faced with these hypotheses and the associated work to
further understand the behaviour of the molecules presented
herein, the project team pragmatically decided to stop work on
these series. The project strategy shifted towards the use of a cell-
based assay as the primary pharmacological assay to bypass this
issue. Results from novel cell-potent series will be communicated
shortly.
Figure 2. Cellular TNFα inhibition in human keratinocytes and in human
peripheral blood mononuclear cells. Colours correspond to distinct chemical
series studied at Galderma. The blue star symbol corresponds to reference
compound Apratastat (1), the red star to compound 3; The correlation line
displays an R2 of 0.88
In conclusion, we have identified novel potent TACE
inhibitors. If compound 31g displayed properties fully
compatible with topical administration and limited systemic
exposure, its relatively weak cellular potency precluded any
further development of this molecule.
To help us understand what the cause of this low cellular
activity, we undertook a non-exhaustive study of enzyme to cell
drop-off from different TACE inhibitor programs in the
literature. We limited our study to compounds being tested in
both an enzymatic and cellular assays and purposefully discarded
data from whole blood assays as the impact of plasma protein
binding could skew the interpretation.8(a) Figure 3 displays data
from 5 different literature references along with compounds from
Table 5.16 The distribution of compounds in the plot coming
from both the literature and our own assays, suggests that other
factors than potency on the enzymatic assay actually govern the
potency on the more complex cell-based model for TACE
inhibition.
References and notes
1.
2.
Belge, K.; Brück, J.; Ghoreschi, K.;
http://f1000.com/prime/reports/m/6/4
(a) Mease,P. J.; Goffe, B. S.; Metz, J.; VanderStoep, A.; Finck, B.;
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M.; Lakshamana, M. G.; Krantikumar, P. Inter. J. Pharm. & H.
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Levin, J. I.; Chen, J. M.; Laasko, L. M.; Du, M.; Schmid, J. ; Xu,
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(a) Duan, J. J.-W.; Chen, L.; Wasserman, Z. R.; Lu, Z.; Liu, R.-Q.;
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Figure 3. Enzymatic and cellular TACE inhibition data taken from 5
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(16a), red (16b), purple (16c), orange (16d) and yellow (16e). Compounds
from Table 5 are depicted as green stars.

10. Representative syntheses of the following compounds are
described in the supplementary material: 31g, 31k, 31f, 29a, 28b,
24.
11. Full characterization of all new compounds are described in the
supplementary material
12. See references cited in: Beillard, A ; Bhurruth-Alcor, Y. ; Bouix-
Peter, C. ; Bouquet, K. ; Chambon, S. ; Clary, L. ; Harris, C.S.;
Millois, C.; Mouis, G.; Ouvry, G.; Pierre, R.; Reitz, A. ; Tomas, L.
Tetrahedron Lett. 2016, 57, 2165
13. Assays are described in the supplementary material
14. Based on
https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecdtg43
2-508.pdf , a test substance with a PIF < 2 predicts: "no
phototoxicity". A PIF >2 and< 5 predicts: "probable
phototoxicity" and a PIF > 5: "phototoxicity”. See Supplementary
Material for more details.
15. Moreira-Tabaka, H.; Peluso, J.; Vonesch, J.-L.; Hentsch, D.;
Kessler, P.; Reimund, J. M.; Dumont, S.; Muller, C. D. PLoS One
2012;7(3):e34184
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20. Binding kinetics were not measured on the molecules described in
this manuscript. However, IK682 a potent TACE inhibitor, analog
to DPC-333 (2) has been described as tight binder Niu, X.;
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Supplementary Material

Graphical Abstract
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Identification of novel TACE inhibitors compatible
with topical application.
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Gilles Ouvry, Yaël Berton, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire Bouix-Peter, Karine
Bouquet, Marilyne Bourotte, Sandrine Chambon, Catherine Comino, Benoît Deprez, Denis Duvert,
Gwenaëlle Duvert, Feriel Hacini-Rachinel, Craig S. Harris, Anne-Pascale Luzy, Arnaud Mathieu,
Corinne Millois, Jonathan Pascau, Artur Pinto, Gaëlle Polge, Arnaud Reitz, Kevin Reversé, Carine
Rosignoli, Nathalie Taquet and Laurent F. Hennequin
Cmpd 31g
TACE IC
12nM