3354 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Letters
phenyl rings of the biphenyl moiety in 12h can rotate
more freely, allowing the P1′ side chain to adjust to the
shape of the S1′ pocket without requiring much energy.
These observations probably account for the difference
in MMP-2 activity between 12g and 12h . The 4-(3,5-
bistrifluoromethylphenyl)benzyl residue in 12i seems
too bulky to fit into the MMP-2 S1′ subsite. In the S1′
pocket of TACE, replacement of the MMP-conserved Tyr
residue, which forms the outer wall of the S1′ region,
by an alanine residue removes the steric interaction
with the 2-trifluoromethyl residue on the distal phenyl
in 12g. Moreover, according to our model, the shape of
the TACE S1′ pocket is different from that of MMP-2,
providing a suitable room for the easy accommodation
of all the P1′ substituents in 12g-i.
Con clu sion . Using an anti-succinate-based macro-
cyclic hydroxamic acid (SP057) as a template, several
biphenylmethyl derivatives were examined at P1′. Among
them, 4-(2-methylsulfonylphenyl)benzyl, 4-(2-trifluo-
romethylphenyl)benzyl, and 4-(3,5-bistrifluoromethyl-
phenyl)benzyl residues were identified to confer potent
pTACE activity with high selectivity versus MMP-1,
MMP-2, and MMP-9. Further profiling for three 4-(2-
trifluoromethylphenyl)benzyl P1′ analogues (12d , 12e,
and 12g) and the 4-(3,5-bistrifluoromethylphenyl)benzyl
P1′ analogue (12i) revealed that these bulky P1′ ana-
logues are also selective over most of other MMPs
screened. The high selectivity of these TACE inhibitors
probably stems from replacement of the MMP-conserved
Tyr residue by an Ala residue in TACE and the shape
difference between TACE and MMPs at the S1′ subsites.
Equally important to their TACE selectivity, these
compounds are potent in the inhibition of TNF-R release
from LPS-stimulated human whole blood. A combina-
tion of 4-(2-trifluoromethylphenyl)benzyl at P1′ and
glycine 4-morpholinylamide or glycine 1-piperazinyl-
amide at P3′-P4′ afforded two attractive TACE inhibi-
tors 12d and 12g which exhibited >100-fold selectivity
over a panel of 11 MMPs and a cellular activity
equipotent to SP057 in WBA (IC50 values of 70 and 60
nM, respectively). Our studies demonstrate that TACE
has a larger S1′ pocket in comparison to MMPs, and
that selective and potent TACE inhibitors can be
achieved by incorporation of appropriate sterically bulky
P1′ residues.
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(15) A homology model of TACE was built based on the crystal
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Ack n ow led gm en t. We thank Sherrill A. Nurnberg,
Dianna L. Blessington, Persymphonie B. Miller, Theresa
M. Dimeo, J ohn Giannaras, Robert J . Collins, Tracy L.
Taylor, and Paul J . Strzemienski for performing pTACE,
MMP, and whole blood assays.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the syntheses of compounds 12a -i and their spec-
troscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
J M0155502