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,
B. M. Differential regulation of TNF-R and IL-1â production from
endotoxin stimulated human monocytes by phosphodiesterase
inhibitors. Mediat. Inflamm. 1992, 1, 411-417. (b) For a review
detailing the in vitro pharmacology of PDE4, see ref 3.
(5) Sekut, L.; Yarnall, D.; Stimpson, S. A.; Noel, L. S.; Bateman-
Fite, R.; Clark, R. L.; Brackeen, M. F.; Menius J . A., J r.;
Connolly, K. M. Antiinflammatory activity of phosphodiesterase
(PDE)-IV inhibitors in acute and chronic models of inflammation.
Clin. Exp. Immunol. 1995, 110, 126-132.
(6) (a) Genain, C. P.; Roberts, T.; Davis, R. L.; Nguyen, M.-H.;
Uccelli, A.; Faulds, D.; Li, Y.; Hedgpeth, J .; Hauser, S. L.
Prevention of autoimmune demyelination in nonhuman primates
by a cAMP-specific phosphodiesterase inhibitor. Proc. Natl. Acad.
Sci. U.S.A. 1995, 92, 3601-3605. (b) Sommer, N.; Lo¨schmann,
P.-A.; Northoff, G. H.; Weller, M.; Steinbrecher, A.; Steinbach,
J . P.; Lichtenfels, R.; Meyermann, R.; Riethmu¨ller, A.; Fontana,
A.; Dichgans, J .; Martin, R. The antidepressant rolipram sup-
presses cytokine production and prevents autoimmune encepha-
lomyelitis. Nature (Medicine) 1995, 1, 244-248.
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
(7) Hanifin, J . M.; Chan, S. C.; Cheng, J . B.; Tofte, S. J .; Henderson,
W. R., J r.; Kirby, D. S.; Weiner, E. S. Type 4 phosphodiesterase
inhibitors have clinical and in vitro antiinflammatory effects in
atopic dermatitis. J . Invest. Dermatol. 1996, 107, 51-56.
(8) Stawiski, M. A.; Rusin, L. J .; Burns, T. L.; Weinstein, G. D.;
Voorhees, J . J . Ro 20-1724: An agent that significantly improves
psoriatic lesions in double-blind clinical trials. J . Invest. Der-
matol. 1979, 73, 261-263.
(9) Woessner, J . F., J r. The family of matrix metalloproteinases.
Ann. N. Y. Acad. Sci. 1994, 732, 11-21.
(10) (a) Conway, J . G.; Wakefield, J . A.; Brown, R. H.; Marron, B.
E.; Sekut, L.; Stimpson, S. A.; McElroy, A.; Menius, J . A.;
J effreys, J . J .; Clark, R. L.; McGeehan, G. M.; Connolly, K. M.
Inhibition of cartilage and bone destruction in adjuvant arthritis
in the rat by a matrix metalloproteinase inhibitor. J . Exp. Med.
1995, 182, 449-457. See also: (b) Hirayama, R.; Yamamoto, M.;
Tsukida, T.; Matsuo, K.; Obata, Y.; Sakamoto, F.; Ikeda, S.
Synthesis and biological evaluation of orally active matrix
metalloproteinase inhibitors. Bioorg. Med. Chem. 1997, 5, 765-
778. (c) Baxter, A. D.; Bird, J .; Bhogal, R.; Massil, T.; Minton,
K. J .; Montana, J .; Owen, D. A. A novel series of matrix
metalloproteinase inhibitors for the treatment of inflammatory
disorders. Bioorg. Med. Chem. Lett. 1997, 7, 879-902.
(11) Hewson, A. K.; Smith, T.; Leonard, J . P.; Cuzner, M. L.
Suppression of experimental allergic encephalomyelitis in the
Lewis rat by the matrix metalloproteinase inhibitor Ro31-9790.
Inflamm. Res. 1995, 44, 345-349.
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
research in this area will be reported in due course.
(12) Bird, J .; Montana, J . New therapeutic approaches to atopic
dermatitis. Exp. Opin. Invest. Drugs 1996, 5, 1173-1180.
(13) Galardy, R. E.; Cassabonne, M. E.; Giese, C.; Gilbert, J . H.;
Lapierre, F.; Lopez, H.; Schaefer, M. E.; Stack, R.; Sullivan, M.;
Summers, B.; Tressler, R.; Tyrrell, D.; Wee, J .; Allen, S. D.;
Castellot, J . J .; Barletta, J . P.; Schultz, G. S.; Fernandez, L. A.;
Fisher, S.; Cui, T.-Y.; Foellmer, H. G.; Grobelny, D.; Holleran,
W. M. Low molecular weight inhibitors in corneal ulceration.
Ann. N. Y. Acad. Sci. 1994, 732, 315-323.
(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.
(16) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.; Date, T.;
Okamura, K.; Inagaki, S. Stereospecific nucleophilic addition
reactions to olefins. Addition of thiols to R,â-unsaturated car-
boxylic acid derivatives. J . Org. Chem. 1991, 56, 6556-6564.
(17) Generated as a 1:1 mixture of diastereomers in 36% yield from
5-phenylpentanal and the dilithium anion of propionic acid.
(18) Capozzi, G.; Roelens, S.; Talami, S. A protocol for the efficient
synthesis of enantiopure â-substituted â-lactones. J . Org. Chem.
1993, 58, 7932-7936.
(19) Cis-isomer 10 (J 3,4 ) 6.6 Hz) and trans-isomer 11 (J 3,4 ) 3.7
Hz). For a reference to â-lactone coupling constants, see: Mulzer,
J .; Kerkmann, T. R-Deprotonation of â-lactones-an example of
a “forbidden” â-elimination. J . Am. Chem. Soc. 1980, 102, 3620-
3622.
(20) PDE4 inhibitory activity was measured as the mean of three
determinations against guinea pig macrophage homogenate
PDE4 according to the methods of Thompson, W. J .; Terasaki,
W. L.; Epstein, P. M.; Strada, S. J . Assay of cyclic nucleotide
phosphodiesterase and resolution of multiple molecular forms
of the enzyme. Adv. Cyclic Nucl. Res. 1979, 10, 69-92.
(21) Inhibitory activity on recombinant human MMP-1, MMP-2, and
MMP-3 (biogenesis) was measured according to the methods of
Knight, C. G.; Willenbrock, F.; Murphy, G. A novel coumarin-
labeled peptide for sensitive continuous assays of the matrix
metalloproteinases. FEBS Lett. 1992, 296, 263-266.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for compounds 1-8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Refer en ces
(1) (a) de Brito, F. B.; Souness, J . E.; Warne, P. J . Type
4
phosphodiesterase inhibitors and their potential in the treatment
of inflammatory disease. Emerging Drugs 1997, 2, 249-268. (b)
Stafford, J . A.; Feldman, P. L. Chronic pulmonary inflammation
and other therapeutic applications of PDE IV inhibitors. Annu.
Rep. Med. Chem. 1996, 31, 71-80.
(2) (a) Beckett, R. P.; Whittaker, M. Matrix metalloproteinase
inhibitors 1998. Exp. Opin. Ther. Patents 1998, 8, 259-282. (b)
Levy, D. E.; Ezrin, A. M. Matrix metalloproteinase inhibitor
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(3) Torphy, T. J . Phosphodiesterase isozymes. Molecular targets for
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