Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template [3]

Full text of DOI:10.1021/jm980567e

J . Med. Chem. 1999, 42, 541-544
541
Sch em e 1a
Du a l In h ibition of P h osp h od iester a se 4
a n d Ma tr ix Meta llop r otein a ses by a n
(Ar ylsu lfon yl)h yd r oxa m ic Acid Tem p la te
Robert D. Groneberg,* Christopher J . Burns,
Matthew M. Morrissette,† J ohn W. Ullrich,‡
Robert L. Morris, Shelley Darnbrough,
Stevan W. Djuric,§ Stephen M. Condon,
Gerard M. McGeehan, Richard Labaudiniere,
Kent Neuenschwander, Anthony C. Scotese, and
J ane A. Kline
Rhoˆne-Poulenc Rorer, SW8, 500 Arcola Road,
Collegeville, Pennsylvania 19426
Received October 6, 1998
In tr od u ction . Two biological targets of considerable
interest in the field of inflammatory disease are phos-
phodiesterase type 4 (PDE4)1 and selected members of
the matrix metalloproteinase (MMP) family, such as
collagenase, gelatinase, and stromelysin.2 PDE4 is a
cyclic AMP-specific phosphodiesterase and is the pre-
dominant isozyme of the inflammatory and immune cell
types.3 Inhibition of PDE4 in these cells elevates intra-
cellular concentrations of c-AMP which produces a
response that has been associated with a general
suppression of proinflammatory cellular activity, includ-
ing the regulation of the proinflammatory cytokine TNF-
R.4 The successful utilization of PDE4 inhibitors has
been demonstrated in preclinical and clinical studies for
disease states such as rheumatoid arthritis (RA),5
multiple sclerosis (MS),6 atopic dermatitis (AD),7 and
psoriasis.8 These encouraging results employing PDE4
inhibitors have, in many respects, been paralleled by
studies using MMP inhibitors.
a
Reagents: (a) NaH, THF, then B; (b) ArSH, cat. BuLi, THF;
(c) TFA/CH2Cl2; (d) ArSH, cat. piperidine, ∆; (e) i. (COCl)2, CH2Cl2,
ii. TMSONH2, CH2Cl2; (f) Oxone, MeOH/H2O.
represented by the â-(arylsulfonyl)hydroxamic acid 1,
that simultaneously inhibit both PDE4 and MMPs 1, 2,
and 3.14
The MMPs are a family of zinc-dependent endopep-
tidases involved in the degradation of the proteins which
comprise the extracellular matrix (ECM). The substrate
specificity of the MMPs divides the group into roughly
three subfamilies: collagenases,gelatinases,and stromely-
sins.9 Remodeling of the ECM is important in maintain-
ing connective tissue and basement membrane integrity
for normal physiology; however, a number of pathologi-
cal conditions involve the overactivation of this class of
enzymes. Small-molecule inhibitors of the MMPs have
been developed,2 and in fact, a selection of these
inhibitors shows positive results in the same disease
models of RA,10 MS,11 AD,12 and psoriasis13 which have
been used to examine the efficacy of PDE4 inhibitors.
Therefore, since it is possible to achieve a beneficial
pharmacological effect by the modulation of two inde-
pendent biological pathways (PDE4 and MMPs), this
creates the intriguing possibility that dual inhibition of
PDE4 and MMPs may offer a therapeutic advantage in
disease states for which models show a positive response
by monotherapy alone. Indeed, in this Communication
we wish to report the discovery of the first compounds,
Ch em istr y. The (arylsulfonyl)hydroxamates were
prepared according to the pathways presented in Scheme
1. Condensation of a phosphonate (A) with an aldehyde
or ketone (B)15 provided the R,â-unsaturated tert-butyl
ester (C). Conversion to the intermediate carboxylic acid
(F ) was accomplished by one of two paths. Lithium
thiolate-catalyzed Michael addition16 (path I) provided
the thiol addition product (D) which was subsequently
deprotected using TFA to yield the carboxylic acid (F ).
Alternatively, hydrolysis of the tert-butyl ester followed
by thiol addition to the unsaturated acid (E) at elevated
temperatures (path II) produced the intermediate
â-(arylthio)carboxylic acid (F ). Conversion to the hy-
droxamic acid (G) was accomplished by reaction of the
acid chloride with excess O-(trimethylsilyl)hydroxyl-
amine. Finally, sulfide oxidation with Oxone provided
the target â-sulfonylhydroxamic acids 1-8 (Table 1).
* Corresponding author. E-mail: robert.groneberg@rp-rorer.com.
† Merck & Co., West Point, PA.
‡ Wyeth-Ayerst Research, Radnor, PA.
§ Abbott Laboratories, Abbott Park, IL.
Coelacanth Corp., East Windsor, NJ .
10.1021/jm980567e CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/09/1999

542 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Communications to the Editor
Sch em e 2a
to sulfonyl hydroxamic acid 1 proceeded without race-
mization using our standard two-step protocol (vide
supra).
R esu lt s a n d Discu ssion . The â-(arylsulfonyl)-
hydroxamic acid template provides potent inhibitors of
either PDE420 or the MMPs21 and also delivers inhibi-
tors with potent activity against both classes of en-
zymes. A preliminary outline of the SAR and the dual
activity that has been revealed is presented in Table 1.
The â-(arylsulfonyl)hydroxamic acids 1-8 have some
structural similarity to an arylsulfonamide class of
MMP inhibitors represented by the clinical candidate
CGS 27023A (13).22 Thus, beginning with compound 2,
which contains a benzyl substituent at the â-position
and has some analogy to 13, we observed potent MMP
a
Reagents: (a) i. (PyS)2, PPh3, CHCl3, ii. Hg(OMs)2, CH3CN,
∆, (66%); (b) p-MeOPhSH, NaOH, iPrOH, (90%); (c) i. (COCl)2,
CH2Cl2, ii. TMSONH2, CH2Cl2, (93%); (d) Oxone, MeOH/THF/H2O,
(95%).
Ta ble 1. Structures and Enzymatic Activities for Compounds
1-8
inhibition but only weak activity against PDE4. Modi-
fication at the â-position revealed that as the chain
length was increased beyond phenethyl (3) to phenpro-
pyl (4) and phenbutyl (5), inhibition of PDE4 was
increased with little change in the MMP profile. This
chain elongation demonstrated for the first time that
the (arylsulfonyl)hydroxamic acid template could be
used to produce compounds with potent inhibitory
activity against MMPs and submicromolar potency
against PDE4.
compda
n
R1 R2
R3 PDE4b MMP-1c MMP-2c MMP-3c
2 (B)
3 (B)
4 (B)
5 (A)
6 (A)
7 (B)
8d (A)
1 (C)
1
2
3
4
4
4
4
4
H
H
H
H
H
H
H
H
9
9
3
0.5
1
4
2
0.02
0.03
0.05
0.02
0.3
0.2
0.6
0.7
H
H
H
H
5
>10
2
H
H
OMe 0.001
>10
>10
H
Me
Me
Me
H
H
H
H
H
9
0.3
0.03
0.05
0.06
0.01
1
0.6
0.5
The next stage of our work revealed that when a 3′-
alkoxy group was added (such as 3’-OMe, compound 6)
to produce the classic 3’,4’-dialkoxyphenyl pharmaco-
2
2
a
Method of preparation in parenthesis: (A) path I, Scheme 1;
phore present in a number of PDE4 inhibitors,1
a
b
(B) path II, Scheme 1; (C) Scheme 2. IC50 (µM), guinea pig
macrophage PDE4; see ref 20. c Ki (µM); MMP-1, fibroblast colla-
dramatic improvement in PDE4 potency was obtained.
This finding is in accordance with a report that certain
(dialkoxyaryl)hydroxamic acids are potent PDE4 inhibi-
tors.23 The dialkoxy substitution pattern, however,
resulted in a dramatic loss of MMP activity, thereby
revealing an apparent pharmacophore “switch” between
the mono- and dimethoxyphenyl analogues of this
template.24 Throughout our work with this template, the
suppressive effect of dialkoxy substitution upon MMP
inhibitory activities was so dominant that the mono-
alkoxy pharmacophore was required to maintain po-
tency against the MMPs.
During further exploration of the SAR at the â-posi-
tion (within the p-alkoxy series), it became apparent
that the incorporation of a second alkyl group (e.g., 7)
produced much weaker PDE4 inhibition. In contrast,
our initial investigation of substitution at the R-position
has been more fruitful, as exemplified by the R-methyl
derivatives 8 and 1. Examination of diastereomer 8
revealed little difference in overall activity when com-
pared to the unsubstituted analogue 5, whereas isomer
1 resulted in a 15-fold improvement in activity against
PDE4 (IC50 ) 0.03 µM) while still maintaining a
favorable MMP profile, particularly for MMP-2 (Ki )
0.01 µM). While the origin of this potency increase
against PDE4 is unknown, it is speculated to be the
result of either a positive hydrophobic interaction within
genase; MMP-2, gelatinase A; MMP-3, stromelysin-1; see ref 21.
d
Anti stereoisomer (2R*,3R*), de 80%.
In general, the yield of each step throughout the
reaction sequence was very good (>80%), and the choice
of pathways was inconsequential apart from two excep-
tions: Preparation of compound 7 (R2 ) Me) required
the use of path II to obtain a satisfactory yield for the
thiol addition step, and preparation of compounds 1 and
8 (R1 ) Me) produced different ratios of the two
diastereomeric products depending upon the path cho-
sen. For 1 and 8, path II produced a poorly separable
50/50 mixture of syn and anti diastereomers following
thiol addition to the (E)-isomer of unsaturated acid E
(where R1 ) Me, R2 ) H, n ) 4). In contrast, path I
provided stereoselective (9:1) anti addition16 to the (E)-
isomer of tert-butyl ester C (R1 ) Me, R2 ) H, n ) 4)
which established the diastereomeric relationship of 8.
For the preparation of isomer 1, an independent
synthesis was used as outlined in Scheme 2. Hydroxy
acid 917 was cyclized using a double activation proce-
dure18 to yield an equimolar mixture of â-lactones (10,
11). The isomers were readily separated by flash column
chromatography and identified by their distinctive
coupling constants.19 Ring opening of 10 with sodium
4-methoxyphenylthiolate in 2-propanol gave clean in-
version to provide carboxylic acid 12. Conversion of 12

Communications to the Editor
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4 543
(4) (a) Molnar-Kimber, K. L.; Yonno, L.; Heaslip, R. J .; Weichman,
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the enzyme active site or a more favorable conforma-
tional bias imparted by the substitution. The ability to
introduce this substitution at the R-position not only
provides an increase in potency with 1 but also affords
the possibility of increasing the metabolic stability of
the hydroxamic acid. Indeed, the stabilizing benefit of
substitution R to hydroxamic acids has been observed
for a number of MMP inhibitors, including several
compounds in the sulfonamide series (i.e., 13), which
has been attributed to a decrease in the hydrolysis and
enzymatic metabolism (via reduction and glucuronida-
tion) of the hydroxamate.22
Several features of the SAR within our â-(arylsulfo-
nyl)hydroxamic acid series suggest that this template
binds in the active site of the MMPs with an orientation
similar to that of the sulfonamides.25 As related to our
series, the key elements of this proposed binding model
are the chelation of the hydroxamic acid to the active-
site zinc and the placement of the aryl sulfone in the
well-defined S1′ hydrophobic pocket. The â-substituent
occupies the shallow S2′ domain and makes limited
contact with the enzyme. This model, therefore, places
a strong dependence upon the aryl sulfone moiety for
binding and limits the effect of the â-substituent.
Indeed, the SAR observed throughout our work with
this template (represented by compounds 2-6) reflects
this aryl sulfone dependence in determining the inhibi-
tory activities and MMP selectivity profile of the series.
Although there is not the same structural data available
for PDE4, the inhibitors of this â-(arylsulfonyl)hydrox-
amic acid series fit a previously proposed active-site
model23 and, likewise, reveal a strong dependence upon
the hydroxamic acid for activity.26
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In conclusion, we have described the discovery and
initial activity profile of a novel â-(arylsulfonyl)hydrox-
amic acid-based structural template. This template can
not only provide potent and selective inhibitors of PDE4
or certain MMPs but, as described herein, also reveal
compounds with potent dual activity (such as 1) de-
pending upon the appropriate scaffold elaboration. The
ability to simultaneously inhibit both PDE4 and MMPs
with a single compound may offer a new pathway for
treating pathologies such as RA, MS, AD, and psoriasis
in which both enzyme families are implicated. Our
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(14) MMP-1, fibroblast collagenase; MMP-2, gelatinase A; MMP-3,
stromelysin-1.
(15) Aldehydes were prepared by Swern oxidation (DMSO, oxalyl
chloride, Et3N) of the alcohol. The required ketone was prepared
by MeLi addition (-78 °C, THF) to the N-methoxy-N-methyla-
mide.
Ack n ow led gm en t. The authors wish to thank Dr.
J ohn E. Souness and Alison J . Capolino for providing
the biological data.
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(19) Cis-isomer 10 (J 3,4 ) 6.6 Hz) and trans-isomer 11 (J 3,4 ) 3.7
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Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
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material is available free of charge via the Internet at http://
pubs.acs.org.
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544 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Communications to the Editor
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J M980567E