α,β-Cyclic-β-benzamido hydroxamic acids: Novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-α converting enzyme (TACE)

Article abstract of DOI:10.1016/j.bmcl.2007.11.059

Selective inhibitors of TNF-α Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl β-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-α in human whole blood, selectivity against a panel of MMPs and oral bioavailability.

Full text of DOI:10.1016/j.bmcl.2007.11.059

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 694–699
a,b-Cyclic-b-benzamido hydroxamic acids: Novel templates
for the design, synthesis, and evaluation of selective inhibitors
of TNF-a converting enzyme (TACE)
Gregory R. Ott,* Naoyuki Asakawa, Zhonghui Lu, Rui-Qin Liu, Maryanne B. Covington,
Krishna Vaddi, Mingxin Qian, Robert C. Newton, David D. Christ, James M. Traskos,
Carl P. Decicco and James J.-W. Duan
Department of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development,
Route 206 and Province Line Road, Princeton, NJ 08543-4000, USA
Received 17 October 2007; revised 14 November 2007; accepted 15 November 2007
Available online 21 November 2007
Abstract—Selective inhibitors of TNF-a Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and
(3R,4S)-tetrahydrofuranyl b-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery
of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated
TNF-a in human whole blood, selectivity against a panel of MMPs and oral bioavailability.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The dysregulation of members of the ADAM (A Disin-
tigrin and Metalloprotease) and MMP (matrix metallo-
protease) family, zinc-dependent proteolytic enzymes
belonging to the metzincin superfamily, has been impli-
cated in numerous pathological conditions including
cancer, osteoarthritis, and rheumatoid arthritis.1
Accordingly, small molecule inhibitors of MMPs and
ADAMs have been extensively investigated as potential
therapies.2 In particular, ADAM-17, also known as
TNF-a Converting Enzyme or TACE, has garnered
considerable attention as the sheddase responsible for
controlling the amount of circulating TNF-a.3 The
anti-TNF biologics entaneracept, inflixamab and ada-
limumab have validated the modulation of TNF-a clin-
ically.4 Thus, as an alternative mediator of TNF-a, small
molecule inhibitors of TACE have been widely re-
searched.5 Furthermore, selective inhibitors are consid-
ered necessary since broad-based MMP inhibitors have
led to negative clinical side effects.6 Though distinct
from the standpoint of the overall sequence homology,
the MMPs and TACE have very similar active sites.7
We8 and others9 have recognized the S1’ pockets of
these enzymes as unique elements and we have used
these features to construct homology models for insights
into designing selective inhibitors.10
Recent efforts from these laboratories directed toward
the search for small molecule, non-peptidic inhibitors
of TACE and MMPs have led to the discovery of several
novel templates.11 Efforts to further expand the struc-
tural diversity, selectivity profile and in vivo properties
of these inhibitors have led to the discovery of con-
strained b-benzamido hydroxamic acid derivatives.12a
Beyond pre-organization of the pharmacologically rele-
vant moieties (i.e. hydroxamic acid, carbonyl and P1’
groups), the constrained b-amino acid may impart dis-
tinct advantages noted for other b-peptides.13 The pur-
ported molecular interactions of the cis-a,b-cyclic-b-
amido hydroxamates are shown in Figure 1.12a The 4-
((2-methylquinolin-4-yl)methoxy)phenyl P1’ moiety
was optimized for potency and selectivity on earlier scaf-
folds, was successfully migrated to the b-amino acid
scaffold, and remains constant for this study of TACE
inhibitors. Herein we report the synthesis and evaluation
of novel TACE inhibitors based upon cis-a,b-cyclic-b-
benzamido hydroxamic acids, with focus on five-mem-
bered ring motifs including substituted (1R,2S)-cyclo-
Keywords: TNF-a; Tumor necrosis factor-a converting enzyme;
TACE; Matrix metalloproteinase; MMP; b-amino acid.
*
Corresponding author at present address: Cephalon, Inc. 145
Brandywine Parkway, West Chester, PA 19380, USA. Tel.: +1 610
738 6861; fax: +1 610 738 6558; e-mail: gott@cephalon.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.059

G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 694–699
695
Figure 1. cis-a,b-cyclic-b-benzamido hydroxamic acid TACE inhibitors.
pentyl, (3S,4S)-pyrrolidinyl and (3R,4S)-tetrahydrof-
uranyl scaffolds.
lation and reprotection of the amine gave 16. Again, the
protected b-amino ester 17 arises from a Curtius rear-
rangement. The free amine 18 was unmasked and cou-
pled to give 19. Preparative HPLC separation of the
enantiomers at this stage gave the desired (3S,4S)-enan-
tiomer. The derived secondary amine common precur-
sor 20a was converted to a variety of functionality
including tertiary amine, sulfonamide, carbamate, and
amide prior to hydroxamic acid formation.
The requisite relative and absolute stereochemistry of
the (1R,2S)-cyclopentane b-benzamido acid core is de-
rived from the commercially available (1R,2S)-2-methyl
cyclohex-4-ene-1,2-dicarboxylate. The benzyl ester 2
(Scheme 1) undergoes an oxidative cleavage-decarboxy-
lative cyclization procedure to afford 3.14,15 Ketone pro-
tection was followed by unmasking of the acid. Curtius
rearrangement16 of 5 installed the protected amine 6.
Removal of the Cbz-group followed by coupling to
812a afforded the amide 9. Deketalization gave the com-
mon precursor 11a suitable for analogue preparation.
Reduction, reductive amination, and fluorination pro-
ceeded smoothly to give 11b–e. Formation of the
hydroxamic acid entailed treating the ester with a solu-
tion of hydroxylamine hydrochloride, methanol, and
potassium hydroxide.
The tetrahydrofuranyl scaffold resulted from a diaste-
reoselective reduction of an appropriate enamine18
(Scheme 3) derived from b-ketoester 22.19 The literature
conditions, when applied to 23, gave the reduction prod-
uct 24 as an inseparable 3:1 mixture of diastereomers.
Debenzylation gave the free amine 25. Chiral HPLC
analysis of 26 revealed an enantiomeric excess of 52%;
the enantiomers were separated on preparative scale.
The desired (3R,4S)-enantiomer was converted to 27.
The racemic pyrrolidine dicarboxylate 14 arises from an
azo-methine-ylid [3+2] cycloaddition of benzylglycine to
benzyl methyl maleate 13 (Scheme 2).17 Global debenzy-
The (1R,2S)-cyclopentane b-amido hydroxamic ana-
logue 1 provided the launching point for further optimi-
zation20 since 1 displayed excellent in vivo properties,
Scheme 1. Reagents and conditions: (a) KMnO4, H2O (99%); (b) AcOH, NaOAc (62%); (c) ethylene glycol, p-TsOH, C6H6 (95%); (d) H2, Pd(OH)2/
C, EtOAc (99%); (e) EtO2CCl, TEA; NaN3, H2O; benzene, reflux; BnOH, p-TsOH, reflux (60%); (f) BOP reagent, DIPEA, DMF (99%); (g) 3 N HCl,
THF; (h) NaBH4, MeOH; (i) Me2NH, NaBH(OAc)3; (j) Et2NSF3, CH2Cl2; (k) NH2OH, KOH, MeOH; (l) TFA, CH2Cl2 (99%).

696
G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 694–699
Scheme 2. Reagents and conditions: (a) N-benzylglycine, (HCHO)n, toluene, reflux (61%); (b) H2, Pd(OH)2/C, MeOH (79–99%) (c) BOC2O, NaOH
(96%); (d) DPPA, TEA, BnOH (73%); (e) 8, BOP, DIPEA, DMF; HPLC separation of enantiomers (30%, >95% ee); (f) TFA, CH2Cl2 (100%); (g)
aldehyde, DIPEA, CH2Cl2, NaBH(OAc)3; (h) acyl chloride, DIPEA, CH2Cl2; (i) sulfonyl chloride, DIPEA, CH2Cl2; (j) alkyl halide, TEA, CH2Cl2;
(k) NH2OH, KOH, MeOH.
boost in cellular potency (ꢀ20-fold for 10 vs. parent 1).
The ketone and hydroxyl substituted analogues (12a–c)
were also potent in the WBA. The insertion of a difluo-
romethylene (12e) as an oxygen isostere22 provided only
a moderate improvement relative to 1. Unfortunately,
the addition of these substituents adversely impacted
the Caco-2 permeability with the exception of the 1,3-
dioxolane analogue 10 (Papp = 1.8 · 10ꢁ6 cm/s); the acid
labile nature of the 1,3-dioxolane precluded further
advancement.
Incorporation of polar functionality into the con-
strained b-amino acid ring system proved to be a suc-
cessful tactic. A boost in cellular potency was realized
with the pyrrolidine analogue 21a. The addition of
either a sulfonyl or acetyl substituent (21b, 21c) did
Scheme 3. Reagents and conditions: (a) (R)-a-methylbenzyl amine,
not alter cell potency. Permeability was low for both
Yb(OTf)3, tol, reflux (48%); (b) NaBH(OAc)3, AcOH, CH3CN (36%,
analogues and consistent with that result, 21b showed
3:1 mixture of diastereomers); (c) H2, Pd(OH)2/C, MeOH (100%); (d)
poor oral bioavailabilty (3%). By altering the nitrogen
8, BOP Reagent, DIPEA, DMF; HPLC separation of enantiomers; (e)
substituent, we could modulate both cell potency (21d)
NH2OH, KOH, MeOH.
and permeability (21g). Toward achieving an optimal
balance between potency and permeability, a variety
most notably oral bioavailability (F = 68% in dogs).12a
of tertiary alkyl amines were evaluated. Analogues
with increased lipophilicity (21i) provided inroads with
Since TACE maturation and localization occurs intra-
cellularly and that intracellular TACE is proteolytically
active,21 the initial objective centered on improving the
moderate potency in the suppression of TNF-a in the
human whole blood assay (WBA, IC50 = 475 nM). Prior
experience suggested that increasing the polarity of the
molecule would drive potency into the desired range
(IC50 < 200 nM). Modeling predicted that the b-amino
acid ring carbons were solvent exposed, thus, this region
was attractive for manipulation.
respect to permeability (Papp = 1.3 · 10ꢁ6 cm/s) while
maintaining
potency
in
the
desired
range
(IC50 = 196 nM). As the size and lipophilicity of the
alkyl substituent increased, a slight erosion in cellular
potency was observed. Unsaturated groups proved
advantageous; 2-methylallyl and propargyl derivatives
21l and 21m gave suitable potency as well as perme-
ability. Importantly, 21m displayed oral bioavailability
in rat (Table 3, F = 25%). Cycloalkyl attachments or
aromatic substituents (21n–p) provided no benefit.
Similar to the pyrrolidine motif, (3R,4S)-tetrahydrof-
uranyl analogue 27, displayed excellent potency in
the cellular assay (WBA IC50 = 33 nM), acceptable
We were gratified to find that the modifications to the 4-
position of the scaffold led to retention of TACE activity
(Table 1, 10, 12a–e) and importantly, added a significant

G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 694–699
Table 1. In vitro data for 1, 10, 12a–e, 21a–p, 27
697
pTACEa
(IC50, nM)
WBAb
(IC50, nM)
MMP-1
(Ki, nM)
MMP-2
(Ki, nM)
MMP-9
(Ki, nM)
Papp
(· 10ꢁ6 cm/s)
c
Ex
X
1
–CH2–
C[-O(CH2)2O-]
–C(O)-
1.0
1.0
1.8
2.3
4.6
<1.0
6.3
6.3
1.6
1.3
2.1
2.7
1.0
1.5
1.6
0.4
1.1
0.94
1.5
0.14
1.0
1.6
2.0
1.0
475
24
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>4948
>3333
2800
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
1851
6.0
1.8
0.2
0.1
0.1
0.1
0.0
10
12a
12b
12c
12d
12e
21a
21b
21c
21d
21e
21f
21g
21h
21i
76
46
>3333
>3333
>3333
>3333
>3333
>3333
>3333
1700
–[a-OH]–
–CH[b-OH]–
–CH[a-NMe2]–
–CF2–
121
193
301
75
d
N–H
N–Ms
–
79
66
0.3
0.2
0.1
0.3
0.4
1.7
0.2
1.3
0.3
0.1
9.8
3.2
0.1
—
N–Ac
NC(O)–i-Pr
N–Piv
68
>3333
>3333
2733
196
223
403
50
N–C(O)OCH3
N–C(O)O–i-Pr
N–Me
1500
>3333
>3333
>3333
>3333
>3333
>3333
>3333
2633
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
N–i-Pr
N–i-butyl
N–Allyl
165
254
97
21j
21k
21l
N–(2-Methylallyl)
N–2-Propynyl
N–c-Bu
210
109
191
880
320
33
21m
21n
21o
21p
27
N–Bn
N–CH2(2-furanyl)
O
>3333
>3333
1.1
1.0
a pTACE IC50 and MMP Ki values are from a single determination.
b Inhibition of TNF-a release in WBA was determined with three donors.
c Papp (A ! B) · 10ꢁ6 cm/s.
d —: Not determined.
Table 2. Selectivity profilesa
Table 3. Rat pharmacokinetic parametersa
Enzyme
21m (Ki, nM)
PK parameters
21mb
27c
pTACE (IC50
MMP-1
MMP-2
)
0.14
>5000
1120
54
IV
dose (mg/kg)
t1/2 (h)
3.3
2.9
5.0
2.1
Cl (L/h/kg)
Vss (L/kg)
AUC (nM · h)
dose (mg/kg)
t1/2 (h)
3.3
1.7
2.3
0.8
MMP-3
MMP-7
6
2234
3.3
4061
5.0
MMP-8
MMP-9
2000
1720
240
PO
3.1
2.9
MMP-10
MMP-12
MMP-13
MMP-14
MMP-15
AUC (nM · h)
F%
567
25%
846
21%
12
490
a Determination of 3 for each dosing group, average value.
b Determined from discrete dosing.
c Determined from n-in-1 cassette dosing.
2800
>7100
a pTACE IC50 and MMP Ki values are from a single determination.
ever, evident for MMPs-3,-7,-12. The full pharmacoki-
netic parameters for lead heterocyclic inhibitors 21m
(pyrrolidinyl) and 27 (tetrahydrofuranyl) are listed in
Table 3. Both display relatively low clearance and
>20% oral bioavailability. Of note, oral half-lives are
>2 h for each analog.
permeability, and oral bioavailability in rats (Table 3,
F = 21%).
Indicative of inhibitors in this series, the selectivity pro-
file of 21m against a panel of MMPs is shown in Table 2.
Inhibitor 21m displays excellent selectivity (>1000-fold)
for MMPs-1,-2,-8,-9,-10,-13,-14,-15. Activity was, how-
In summary, we have evaluated (1R,2S)-cyclopentanyl,
(3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl b-

698
G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 694–699
10. Recently, other potential avenues for design of selective
TACE inhibitors have been reported, see Lukacova, V.;
Zhang, Y.; Kroll, D. M.; Raha, S.; Comez, D.; Balaz, S.
A. J. Med. Chem. 2005, 48, 2361.
benzamido hydroxamic acids as privileged templates for
the discovery of selective inhibitors of TACE. In partic-
ular, inhibitors 21m and 27 proved to be potent for
pTACE, selective over a panel of MMPs, potent in the
suppression of LPS-induced TNF-a in human whole
blood and orally bioavailable.
11. For leading references see (a) Xue, C.-B.; Voss, M. E.;
Nelson, D. J.; Duan, J. J.-W.; Cherney, R. J.; Jacobson,
I. C.; He, X.; Roderick, J.; Chen, L.; Corbett, R. L.;
Wang, L.; Meyer, D. T.; Kennedy, K.; DeGrado, W. F.;
Hardman, K. D.; Teleha, C. A.; Jaffee, B. D.; Liu, R.-Q.;
Copeland, R. A.; Covington, M. B.; Christ, D. D.;
Trzaskos, J. M.; Newton, R. C.; Magolda, R. L.; Wexler,
R. R.; Decicco, C. P. J. Med. Chem. 2001, 44, 2636; (b)
Duan, J. J.-W.; Chen, L.; Wasserman, Z. R.; Lu, Z.; Liu,
R.-Q.; Covington, M. B.; Qian, M.; Hardman, K. D.;
Magolda, R. L.; Newton, R. C.; Christ, D. D.; Wexler,
R. R.; Decicco, C. P. J. Med. Chem. 2002, 45, 4954; (c)
Xue, C.-B.; He, X.; Roderick, J.; Corbett, R. L.; Duan,
J. J.-W.; Liu, R.-Q.; Covington, M. B.; Newton, R. C.;
Trzaskos, J. M.; Magolda, R. L.; Wexler, R. R.; Decicco,
C. P. Bioorg. Med. Chem. Lett. 2003, 13(24), 4293; (d)
Xue, C.-B.; Chen, X. T.; He, X.; Roderick, J.; Corbett,
R. L.; Ghavimi, B.; Liu, R.-Q.; Covington, M. B.; Qian,
M.; Ribadeneira, M. D.; Vaddi, K.; Trzaskos, J.;
Newton, R. C.; Duan, J. J.-W.; Decicco, C. P. Bioorg.
Med. Chem. Lett. 2004, 14, 4453; (e) Gilmore, J. L.;
King, B. W.; Harris, C.; Maduskuie, T.; Mercer, S. E.;
Liu, R.-Q.; Covington, M. B.; Qian, M.; Ribadeneria, R.;
Vaddi, K.; Trzaskos, J. M.; Newton, R. C.; Decicco, C.
P.; Duan, J. J.-W. Bioorg.Med. Chem. Lett. 2006, 16,
2699; (f) Cherney, R. J.; Mo, R.; Meyer, D. T.;
Hardman, K. D.; Liu, R.-Q.; Covington, M. B.; Qian,
M.; Wasserman, Z. R.; Christ, D. D.; Trzaskos, J. M.;
Newton, R. C.; Decicco, C. P. J. Med. Chem. 2004, 47,
2981.
Acknowledgments
We thank John Giannaras, Sherrill Nurnberg, and Paul
Strzemienski for assistance in running in vitro assays,
Bernice Brogdon, Bing Lu, Hang Zheng, and Jingtao
Wu for assistance in pharmacokinetic studies and Maria
Ribadeneira for Caco-2 assay. The authors thank Sarah
Traeger and Tom Scholz for NMR analysis, Al Mical
for chiral HPLC separation of intermediates, and
George Emmett for intermediate preparation.
References and notes
1. (a) Stocker, W.; Grams, F.; Baumann, U.; Reinemer, P.;
Gomis-Ruth, F.-X.; McKay, D. B.; Bode, W. Protein
Sci. 1995, 4, 823; (b) Hooper, N. M. FEBS Lett. 1994,
354, 1.
2. For recent reviews see (a) Skiles, J. W.; Gonnella, N. C.;
Jeng, A. Y. Curr. Med. Chem. 2004, 11, 2911; (b) Skiles,
J. W.; Gonnella, N. C.; Jeng, A. Y. Curr. Med. Chem.
2001, 8(4), 425; (c) Moss, M. L.; White, J. M.; Lambert,
M. H.; Andrews, R. C. Drug Discovery Today 2001, 6(8),
417.
12. For preliminary accounts of this work see: (a) Duan, J. J.-
W.; Chen, L.; Lu, Z.; Xue, C.-B.; Liu, R.-Q.; Covington,
M. B.; Qian, M.; Wasserman, Z. R.; Vaddi, K.; Christ, D.
D.; Trzaskos, J. M.; Newton, R. C.; Decicco, C. P. Bioorg.
Med. Chem. Lett. 2007. doi:10.1016/j.bmcl.2007.10.093;
(b) Ott, G. R.; Lu, Z.; Asakawa, N.; Covington, M. B.;
Qian, M.; Liu, R.-Q.; Newton, R. C.; Christ, D. D.;
Decicco, C. P.; Duan, J. J.-W. Abstracts of Papers, 228th
ACS National Meeting, Philadelphia, PA, USA, 2004,
August 22–26, MEDI-324; (c) Chen, X.-T.; Ghavimi, B.;
Corbett, R. L.; Xue, C.-B.; Liu, R.-Q.; Covington, M. B.;
Qian, M.; Vaddi, K. G.; Christ, D. D.; Hartman, K. D.;
Ribadeneira, M. D.; Trzaskos, J. M.; Newton, R. C.;
Decicco, C. P.; Duan, J. J.-W. Bioorg. Med. Chem. Lett.
2007, 17(7), 1865.
3. Black, R. A. Int. J. Biochem. Cell Biol. 2002, 34(1), 1.
4. (a) Moreland, L. W.; Baumgartner, S. W.; Schiff, M. H.;
Tindall, E. A.; Fleischmann, R. M.; Weaver, A. L.;
Ettlinger, R. E.; Cohen, S.; Koopman, W. J.; Mohler, K.;
Widmer, M. B.; Blosch, C. M. N. Engl. J. Med. 1997, 337,
141; (b) Lipsky, P. E.; van der Heijde, D. M. F. M. E.;
Clair, W. St.; Furst, D. E.; Breedveld, F. C.; Kalden, J. R.;
Smolen, J. S.; Weisman, M.; Emery, P.; Feldmann, M.;
Harriman, G. R.; Maini, R. N. N. Engl. J. Med. 2000, 343,
1594; (c) Machold, K. P.; Smolen, J. S. Exp. Opin. Bio.
Ther. 2003, 3, 351.
5. For a recent review see Skotnicki, J. S.; Levin, J. I. Ann.
Rep. Med. Chem. 2003, 38, 153.
6. Levitt, N. C.; Eskens, F. A. L. M.; O’Byrne, K. J.;
Propper, D. J.; Denis, L. J.; Owen, S. J.; Choi, L.;
Foekens, J. A.; Wilner, S.; Wood, J. M.; Nakajima, M.;
Talbot, D. C.; Steward, W. P.; Harris, A. L.; Verweij, J.
Clin. Cancer Res. 2001, 7, 1912.
13. Seebach, D.; Beck, A. K.; Bierbaum, D. Chem. Biodiv.
2004, 1(8), 1111.
14. All intermediates are in accordance with their H NMR
1
and mass spectrometry data. In addition, all final targets
are consistent with 1H NMR, high resolution mass
spectrometry and combustion analysis.
7. Maskos, K.; Fernandez-Catalan, C.; Huber, R.; Bou-
renkov, G. P.; Bartunik, H.; Ellestad, G. A.; Reddy,
P.; Wolfson, M. F.; Rauch, C. T.; Castner, B. J.;
Davis, R.; Clarke, H. R. G.; Petersen, M.; Fitzner, J.
N.; Douglas, P. C.; March, C. J.; Paxton, R. J.; Black,
R. A.; Bode, W. Proc. Natl. Acad. Sci. U.S.A. 1998,
95(7), 3408.
8. Wasserman, Z. R.; Duan, J. J.-W.; Voss, M. E.;
Xue, C.-B.; Cherney, R. J.; Nelson, D. J.; Hardman,
K. D.; Decicco, C. P. Chem. & Biol. 2003, 10(3),
215.
9. For leading references see (a) Chen, J. M.; Jin, G.; Sung,
A.; Levin, J. I. Bioorg. Med. Chem. Lett. 2002, 12, 1195;
(b) Robinson, R. P.; Laird, E. R.; Blake, J. F.; Bordner, J.;
Donahue, K. M.; Lopresti-Morrow, L. L.; Mitchell, P. G.;
Reese, M. R.; Reeves, L. M.; Stam, E. J.; Yocum, S. A. J.
Med. Chem. 2000, 43, 2229.
15. For a similar sequences, see: (a) Gais, H. J.; Buelow, G.;
Zatorski, A.; Jentsch, M.; Maidonis, P.; Hemmerle, H. J.
Org. Chem. 1989, 54, 5115; (b) Cheetham, R.; Deo, P.;
Lawson, K.; Moseley, D.; Mound, R.; Pilkington, B. Pest.
Sci. 1997, 50, 329.
16. For examples of cyclic b-amino acids prepared using a
Curtius rearrangement, see: Bolm, C.; Schiffers, I.; Ato-
diresei, I.; Hackenberger, C. P. R. Tetrahedron: Asymme-
try 2003, 14, 3455.
17. (a) Grigg, R.; Thianpatanagul, S. J. Chem. Soc. Chem.
Commun. 1984, 180; (b) Joucia, M.; Mortier, J. J. Chem.
Soc., Chem. Commun. 1985, 1566.
18. Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61(16),
5557.

G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 694–699
699
19. Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30,
6129.
20. Details of the pTACE (porcine TACE), MMP, human
whole blood (WBA) assays have been reported, see Ref.
11a. Porcine TACE was used due to availability and
homology to human TACE.
21. (a) Schlondorff, J.; Becherer, J. D.; Blobel, C. P. Biochem.
J. 2000, 347, 131; (b) Solomon, K. A.; Covington, M. B.;
DeCicco, C. P.; Newton, R. C. J. Immunol. 1997, 159,
4524.
22. For a review article see O’Hagen, D.; Rsepa, H. S. Chem.
Commun. 1997, 645.