Discovery of novel cyanamide-based inhibitors of cathepsin C

Article abstract of DOI:10.1021/ml100212k

The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.

Full text of DOI:10.1021/ml100212k

pubs.acs.org/acsmedchemlett
Discovery of Novel Cyanamide-Based Inhibitors
of Cathepsin C
ꢀ
Dramane Laine,* Michael Palovich, Brent McCleland, Emilie Petitjean, Isabelle Delhom,
Haibo Xie, Jianghe Deng, Guoliang Lin, Roderick Davis, Anais Jolit, Neysa Nevins,
Baoguang Zhao, Jim Villa, Jessica Schneck, Patrick McDevitt, Robert Midgett, Casey Kmett,
Sandra Umbrecht, Brian Peck, Alicia Bacon Davis, and David Bettoun
GlaxoSmithKline, Respiratory CEDD, 709 Swedeland Road, P.O. Box 1539, King of Prussia, Pennsylvania 19406-0939,
United States
ABSTRACT The discovery of potent and selective cyanamide-based inhibitors of
the cysteine protease cathepsin C is detailed. Optimization of the template with
regard to plasma stability led to the identification ofcompound 17, a potent cathep-
sin C inhibitor with excellent selectivity over other cathepsins and potent in vivo
activity in a cigarette smoke mouse model.
KEYWORDS Cathepsin C inhibitors, cyanamides, potent, selective, cigarette smoke
athepsin C (also known as dipeptidyl peptidase I,
hDPPI, EC: 3.4.14.1) is a lysosomal cysteine dipep-
tidyl aminopeptidase from the papain family of pro-
access beyond the S2 site. The requirements for substrate
recognition and cleavage by cathepsin C have been estab-
lished and showed that the enzyme can accept a broad
variety of peptide substrates.1,2,19,20 The crystal structure
of cathepsin C with a covalent inhibitor has also been
reported.21 Because of the positioning of the S1 site on the
surface of the enzyme, P1 residues bearing a hydrophobic,
basic, acidic, or polar side chain are accommodated. Aliphat-
ic, hydrophobic, polar, and acidic residues are accepted in
the S2 pocket with a preference for small aliphatic residues.
The presence of a terminal N-amino group is necessary to
anchor the substrate in the active site via an ionic interaction
with Asp1. The enzyme cleaves two-residue units from the
substrate until it reaches a stop sequence, which could be an
arginine or lysine in P2, a proline in P1 or P10, or an iso-
leucine in P1.
C
teases. As its name suggests, cathepsin C removes dipeptide
moieties from the N termini of target proteins.1,2 The
enzyme is constitutively produced in many tissues with the
highest expression levels found in lung, kidney, liver, and
spleen.3 There is increasing evidence that cathepsin C plays
a key role in a variety of diseases, including sepsis,4 arthritis,5
and other inflammatory disorders.6-12 From knockout mice
studies, it appears that cathepsin C is coexpressed and acts
as a physiological activator of the neutrophil-derived serine
proteases: neutrophil elastase, cathepsin G and proteinase 3,5
the mast cell chymase and trypase,13 and the lymphocytes
derived granzymes A and B.14 Once activated, these proteases
are capable of degrading various extracellular matrix compo-
nents, which can lead to tissue damage and chronic inflam-
mation. Thus, inhibitors of cathepsin C could potentially be
useful therapeutics for the treatment of neutrophil-dominated
inflammatory diseases such as chronic obstructive pulmonary
disease (COPD) and cystic fibrosis (CF).15,16
A variety of peptidyl derivatives have been reported in the
literature as cathepsin C inhibitors. It comprised mainly di- or
tripeptide derivatives functionalized with an electrophilic group,
such as a vinyl sulfone,22-24 an acyloxymethyl ketone,23
fluoromethyl ketone,23 a conjugated ester,24 a nitrile,24-26
a
a
An X-ray crystal structure of cathepsin C has been deter-
mined and showed that, unlike other cysteine proteases, the
enzyme is composed of four identical subunits, each con-
taining three chains: a heavy chain, a light chain, and an
exclusion domain.17 A catalytic ion pair near the scissile
peptide bond is formed by the Cys234 and His381
residues.18 The S1 site is not a well-defined pocket but rather
a surface located near the solvent surface. The S2 pocket is
deep and hydrophobic and contains a chloride ion and two
solvent molecules at the bottom. The N-terminal Asp 1
residue of the exclusion domain is placed at the entrance
of the S2 pocket. The exclusion domain is unique to cathep-
sin C and key to the substrate specificity of the enzyme as
it prevents endopeptidase activity by blocking substrate
phosphine group,27 a semicarbazide moiety,28 or a diazo-
methylketone.29 A few peptides,30-32 or the nonspecific
cysteine protease inhibitor, E64, have also been found to inhibit
cathepsin C.32 To date, nonpeptidic inhibitors of cathepsin C
have not been disclosed. Several series of cyanamide-based
inhibitors of cysteinyl cathepsins have been previously reported
from these laboratories33 or elsewhere.34,35 These compounds
displayed nanomolar activity for cathepsins K or L, but no
activity for cathepsin C has ever been disclosed. On the basis
Received Date: September 13, 2010
Accepted Date: November 3, 2010
Published on Web Date: November 10, 2010
r
2010 American Chemical Society
142
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|

pubs.acs.org/acsmedchemlett
Table 1. Illustrative Examples of SAR Study
a NT, not tested. b Values are the mean of two or more independent assays.
of that knowledge, we decided to examine the potential of
cyclic cyanamides as cathepsin C inhibitors. Our aim was to
identify molecules that could be further evaluated in vivo in a
cigarette smoke mouse model. These compounds needed to
be selective over the structurally related cysteine proteases:
cathepsins L, S, B, and K, which have all been reported to
play vital roles in number of important physiological and
pathological processes.36
An initial set of compounds was rapidly prepared by
cyanation of cyclic amine building blocks, available either
r
2010 American Chemical Society
143
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|

pubs.acs.org/acsmedchemlett
from commercial sources or from our compound collection.
Illustrative compounds of this initial structure-activity re-
lationship (SAR) study are shown in Table 1. The 3-phenethyl
derivative 1 displayed an encouraging basal cathepsin C
activity with a pIC50 of 5.7 but no selectivity over the other
cathepsins, whereas the unsubstituted pyrrolidine nitrile 2
and the piperidine analogue 3 were inactive. These results
prompted us to prepare a variety of 3-substituted pyrrolidine
nitriles to examine different linkers between the 5-mem-
bered ring and the phenyl group. This approach led to the
identification of the sulfonamine enantiomers 4 and 5. Both
molecules displayed similar activity at cathepsin C (pIC50 6.5),
which was slightly superior to that of the corresponding
amide 6 or urea 7. Because of the higher selectivity of 5 over
other cathepsins, the S configuration at C-3 appeared more
promising and was thus selected for further lead optimiza-
tion. Further functionalization of the sulfonamide phenyl led
to the identification of more potent molecules, such as the
bromo derivative 8 and the dimethoxy 9 (pIC50 of 8.1 and
8.0, respectively). Subsequent replacement of the methoxy
group of 9 with bromide atoms gave 10 with excellent
cathepsin C activity (pIC50 > 9.4) and good selectivity. Meta-
bolic stability, however, turned out to be a problem for 8, 9,
and 10 as the compounds displayed high rat plasma turnover
(<25% of compound remaining after 30 min of incubation,
Table 1) despite being stable in human plasma (data in the
Supporting Information). As our primary in vivo models
were based in rodent, we needed to ascertain the reason
for this instability. Our initial suspicions were that part of the
instability was due to the high reactivity of the nitrile war-
head. To test this hypothesis, compounds bearing an alde-
hyde (11) and a BOC group (12) in place of the nitrile moiety
were examined. We found that although neither compound
inhibited cathepisn C, both were indeed stable in rat plasma.
Studies were then initiated to ascertain the mechanism of
the instability. To identify the cause of the degradation of the
compounds in the rat, a series of experiments examining
the stability of 8, in the presence of various additives, were
conducted. No degradation was observed in the presence of
rat serum albumin, free cysteine, or glutathione or when 8
was incubated in the presence of a broad spectrum esterase
inhibitor (see the graphs in the Supporting Information).
We concluded from these studies that the instability of
the compounds in rat plasma probably involved an esterase
acting on the nitrile group. Next, we hypothesized that we
could reduce the rate of reaction with the esterase by
reducing the electrophilicity and steric accessibility of the
nitrile head. To this end, we examined the introduction of a
methyl group at the C-5 position while keeping the optimal
C-3 configuration. As shown in Table 1, this approach led to
the identification of the (5R)-methyl derivatives 13 and 14
with improved plasma stability. Both compounds, however,
did not inhibit cathepsin C and had little or no activity at
other cathepsins. The corresponding (5S)-methyl derivatives
15 and 16 were also prepared and displayed much better
activity at cathepsin with pIC50 values of 6.8 and 6.9, respec-
tively. In an analogous manner to the previously described
functionalization of 5, the introduction of 2,5-dibromo sub-
stituents on the phenyl sulfonamide group led to a significant
Scheme 1a
a Reagents and conditions: (a) MeOH, AcCl. (b) (BOC)2O, TEA. (c) TBSCl,
imidazole. (d) LiBH4. (e) MsCl, TEA. (f) LiEt3BH. (g) TBAF, THF. (h) Same
as e. (i) tBuNþN3-, CH3CN. (j) H2, Pd/C, MeOH. (k) 2,5-DiBrPhSO2Cl,
TEA. (l) 4 N HCl, dioxane. (m) BrCN, DCM.
increase in potency, and 17 was identified with a pIC50 of 8.5
and good stability in rat plasma. At that point of our investi-
gation, the decision was made to focus on a mouse in vivo
model for further pharmacological evaluation. The stability
of 17 was therefore assessed in mouse plasma and found
to be somewhat lower (57% of compound remaining after
30 min) than in rat. Although suboptimum, this level of
stability was deemed to be adequate for further in vivo
pharmacological evaluation.
The methods of preparation of compounds 1-16 are
shown in the Supporting Information. Compound 17 was
synthesized according to the route outlined in Scheme 1.
Esterification of (4S)-4-hydroxy-D-proline 18 in acidic metha-
nol, followed by successive conversion of the amine to the
corresponding BOC derivative then of the secondary alcohol
to a TBS ether gave, after reduction of the methyl ester
moiety, the primary alcohol 19. Subsequent conversion of 19
to the corresponding methanesulfonate ether followed by
treatment with lithium triethyl borohydride produced the
(5S)-methyl derivative 20. Further desilylation of 20 with
TBAF gave a secondary alcohol intermediate, which was
transformed to the azide 21 with inversion of configuration
at C-3 by activation of the alcohol as a methanesulfonate
ether and treatment with t-butyl ammonium azide. Palladium-
catalyzed hydrogenation of 21 followed by treatment with
2,5-dibromobenzenesulfonyl chloride gave the derivative 22.
Subsequent removal of the BOC protecting group with 4 N HCl
in dioxane, followed by treatment with cyanogen bromide,
resulted in the formation of 17.
The cocrystal structure of 17 bound in the cathepsin C
active site indicates that the nitrile covalently reacts with cat-
alytic Cys234 forming a thioimidate complex with a hydro-
gen bond to oxyanion hole residue Gln228 (Figure 1). The
sulfonamide forms a hydrogen bond to the backbone NH of
Gly277 and links the pyrrolidine nitrile template to the 2,5-
dibromophenyl moiety, which trajects into the S2 pocket.
The 5-methyl restricts the conformation of the pyrrolidine
ring and interacts with the back wall of the binding site.
r
2010 American Chemical Society
144
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|

pubs.acs.org/acsmedchemlett
The in vivo pharmacokinetic (PK) properties of 17 were
assessed in several species as shownin Table 2. In the mouse,
17 displayed variable PKs. In three out of four mice dosed
orally, low exposure and low bioavailability were observed,
whereas one showed high bioavailability and ∼9-fold higher
exposure. Variable data also were obtained with regard to
plasma clearance when eight separate mice were adminis-
tered 17 intravenously with a 50% frequency of mice de-
monstrating high and low plasma clearance of 17, respec-
tively. Similar results were observed with other structurally
related pyrollidine nitriles (data not shown) and may be
indicative of polymorphic metabolism-mediated clearance
of this class of compounds. In an attempt to determine
whether these findings were mouse-specific, we also exam-
ine 17 in the rat and dog. In rat, the compound demon-
strated low oral exposure and bioavailability, likely due to
high plasma clearance. Overall, the PK profile of 17 was
improved in dog as compared to rat and to the apparent
extensively metabolized mouse population with moderate
clearance, systemic exposure, and bioavailability observed
consistently across all of the dogs evaluated.
The effect of oral administration of compound 17 on
cathepsin C inhibition was examined in mice (Figure 2).
Time-course activity studies at a high dose (30 mg/kg)
showed statistically significant inhibition (35%) of cathepsin
C activity by 17 in plasma at 30 min (Figure 2a) and in lung
homogenate at 0.5, 1.5, and 3 h (32, 16, and 28%, Figure 2b).
The compound was not detected in plasma at any of the time
points of the plasma study. These results showed that in vivo
inhibition of cathepsin C by 17 is achievable after oral
dosing; yet, the level of engagement of the enzyme might be
suboptimal because of the variable PK profile and short half-
life (20 min) of 17 in mice. To bypass microsomal clearance
and potentially observe greater effects in the lung, it was
decided to dose topically to the lung via intranasal delivery.
When dosed intranasally at 30 mg/kg, 17 showed a signifi-
cant time-dependent inhibition of cathepsin C activity in
lung homogenate (53, 66, and 85% at 0.5, 1.5, and 3 h),
which was much greater than when a similar dose was
administered orally (Figure 3a). At the optimum time point
of 30 min, compound 17 demonstrated a dose-related inhi-
bition of cathepsin C with an ED50 of 20 mg/kg (Figure 3b).
These results demonstrated that intranasal delivery was a
superior route of administration for 17 with respect to the
Figure 1. X-ray crystal structure of 17.
Table 2. PK Profile of 17
species
dose (iv/po; mg/kg)
Fb (%)
AUC (po, ng h/mL)
Vdss (L/kg)
3.1 ( 2.0
Clpc (mL/min/kg)
t1/2 (h)
rata
moused
doga
1/2
8 ( 3
7 ( 4
162 ( 14
0.2 ( 0.1
5/20
5/10
1, 7, 75, 2
9, 11.5, 89, 10
0.4, 1.8, 1.8, 0.9
16, 90, 137, 33
0.4, 0.2, 0.2, 0.3
20 ( 7
1180 ( 606
1.3 ( 0.2
29 ( 9
0.7 ( 0.1
a Values are the mean of two or more independent assays. b F, percent bioavailability. c Clp, systemic plasma clearance. d Individual values listed due to variability.
Figure 2. In vivo effect of 17 following oral administration. (a) Time course of cathepsin C activity in plasma as measured by the cleavage of
(H-Gly-Arg)2 R110 (10 μM) in mice administered orally with 17 (30 mg/kg, n = 5). (b) Time course of cathepsin C activity as measured by the
cleavage of (H-Gly-Arg)2 R110 (10 μM) in crude lung homogenate from C57BL/6J mice administered orally with 17 (30 mg/kg, n = 5).
r
2010 American Chemical Society
145
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|

pubs.acs.org/acsmedchemlett
Figure 3. In vivo effect of 17 following intranasal administration. (a) Time course of cathepsin C activity as measured by the cleavage of
(H-Gly-Arg)2 R110 in crude lung homogenate from C57BL/6 mouse lungs collected after intranasal treatment with 17 (n = 5). (b) Thirty
minute dose response of 17 administered to C57BL6/J mice intranasally and measured in crude lung homogenate (n = 5). (c) Cathepsin
C activity as measured by the cleavage of (H-Gly-Arg)2 R110 (10 μM) in crude lung homogenate from BALB/c mice after exposure to cigarette
smoke for 3 days and 17 (30 mg/kg) administered intranasally daily for 4 days (n = 5).
level of engagement of the enzyme in the lung, and the deci-
sion was made to use this mode of delivery to evaluate the
compound in a 5 day cigarette smoke mouse model (Figure 3c).
In this study, mice were administered 17 on day 1 (30 mg/kg)
and then for 3 further days were dailyadministered similar doses
of 17 immediately followed by cigarette smoke inhalation. On
the fifth day, lung homogenate was collected and evaluated. A
significant increase in cathepsin C activity induced by cigarette
smoke was observed in the vehicle and smoke-treated animal
group. The level of cathepsin C activity of the 17-treated group
was significantly reduced to levels below that of the vehicle-only
treated group. Taken together, these data indicate that com-
pound 17 is an effective cathepsin C inhibitor in mice when
administered intranasally.
In conclusion, a novel series of cyanamide-based inhibi-
tors of the cysteine protease cathepsin C were discovered.
After optimization of the structural features with regard to
plasma stability, 17 was identified as a potent cathepsin C
inhibitor with excellent selectivity over other cathepsins.
Crystallographic studies with 17 showed that a covalent
bond was formed between the nitrile group and the Cys
234 residue in the active site of the enzyme. Because of its
variable PK profile and short half-life, 17 displays minimal
activity in mice when administered orally. In a cigarette
smoke model, the increased activity of cathepsin C was
significantly reduced by intranasal administration of 17. The
significance of these findings is currently being investigated in
our laboratory. Further accounts on this novel series will be the
subject of future publications.
Accession Codes: The atomic coordinates for the X-ray crystal
structure of 17 have been deposited with the RCSB Protein Data
Bank under the accession code 3PDF.
AUTHOR INFORMATION
Corresponding Author: *Tel: 1-610-270-7889. Fax: 1-610-270-
4451. E-mail: dramane.i.laine@gsk.com.
REFERENCES
(1)
McGuire, M. J.; Lipsky, P. E.; Thiele, D. L. Purification and
characterization of dipeptidyl peptidase I from human
spleen. Arch. Biochem. Biophys. 1992, 295, 280–288.
Tran, T. V.; Ellis, K. A.; Kam, C.-M.; Hudig, D.; Powers, J. C.
Dipeptidyl peptidase I: Importance of progranzyme activation
sequences, other dipeptide sequences, and the N-terminal
amino group of synthetic subtrates for enzyme activity. Arch.
Biochem. Biophys. 2002, 403, 160–170.
(2)
(3)
(4)
(5)
Kominami, E.; Ishido, D.; Muon, D.; Sato, N. The primary
structure and distribution of cathepsin C. Biol. Chem. Hoppe
Seyler. 1992, 373, 367–373.
Mallen-St. Clair, J.; Pham, C. T.; Villalta, S. A.; Caughey, G. H.;
Wolters, P. J. Mastcell dipeptidyl peptidase I mediates survival
from sepsis. J. Clin. Invest. 2004, 113, 628–634.
Adkison, A. M.; Raptis, S. Z.; Kelley, D. G.; Pham, C. T. N.
Dipeptidyl peptidase I activates neutrophil-derived serine
proteases and regulates the development of acute experi-
mental arthritis. J. Clin. Invest. 2002, 109, 363–371.
Methot, N.; Rubin, J.; Guay, D.; Beaulieu, C.; Ethier, D.; Reddy,
T. J.; Riendeau, D.; Percival, M. D. Inhibition of the Activation of
Multiple Serine Proteases with a cathepsin C Inhibitor Requires
Sustained Exposure to Prevent Pro-enzyme Processing. J. Biol.
Chem. 2007, 282, 20836–20846.
Methot, N.; Guay, D.; Rubin, J.; Ethier, D.; Ortega, K.; Wong, S.;
Normandin, D.; Beaulieu, C.; Reddy, T. J.; Riendeau, D.; Percival,
M. D. In Vivo Inhibition of Serine Protease Processing Requires a
High Fractional Inhibition of cathepsin C. Mol. Pharmacol. 2008,
73, 1857–1865.
(6)
(7)
(8)
SUPPORTING INFORMATION AVAILABLE General meth-
ods of preparation of compound 1-22 (Table 1 and Scheme 1),
general methods for the recombinant cathepsins in vitro assays
(Table1), procedures for the plasma stability studies (Table 1), data
for the human plasma stability studies and the graphs of the rat
plasma stability studies for compounds 8, 11, and 12, protocols for
the in vivo experiments described in Figures 2 and 3, and exposure
levels for Figure 2a. This material is available free of charge via the
Internet at http://pubs.acs.org.
McGuire., M. J.; Lipsky, P. E.; Thiele, D. L. Generation of Active
Myeloid and Lymphoid Granule Serine Proteases Requires
Processing by the Granule Thiol Protease Dipeptidyl Petidase
I. J. Biol. Chem. 1993, 268, 2458–2467.
r
2010 American Chemical Society
146
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|

pubs.acs.org/acsmedchemlett
(9)
Mabee, C. L; McGuire, M. J.; Thiele, D. L. Dipeptidyl Peptidase I
and Granzyme A Are Coordinately Expressed During CD8þ T
Cell Development and Differentiation. J. Immunol. 1998, 160,
5880–5885.
inhibitors of cathepsin C. Bioorg. Med. Chem. Lett. 2009, 19,
5392–5396.
(27) Mucha, A.; Pawelczak, M.; Hurek, J.; Kafarski, P. Synthesis
and activity of phosphinic tripeptide inhibitors of cathepsin
C. Bioorg. Med. Chem. Lett. 2004, 14, 3113–3116.
(28) Bondebjerg, J.; Fuglsang, H.; Valeur, K. R.; Kaznelson,
D. W.; Hansen, J. A.; Pedersen, R. O.; Krogh, B. O.; Jensen,
B. S.; Lauritzen, C.; Petersen, G.; Pedersen, J.; Naerum,
L. Novel semicarbazide-derived inhibitors of human di-
peptidyl peptidase I (hDPPI). Bioorg. Med. Chem. 2005, 13,
4408–4424.
(29) Green, D. J.; Shaw, E. Peptidyl Diazomethyl Ketones Are
specific Inactivators of Thiol Proteinases. J. Biol. Chem.
1981, 256, 1923–1928.
(30) Horn, M.; Pavlik, M.; Doleckova, L.; Baudys, M.; Mares, M.
Arginine-based structures are specific inhibitors of cathepsin
C. Eur. J. Biochem. 2000, 267, 3310–3336.
(10) Thiele, D. L.; McGuire, M. J.; Lipsky, P. E. A Selective Inhibitor
of Dipeptidyl Peptidase I Impairs Generation of CD8þ T Cell
Cytotoxic Effector Function. J. Immunol. 1997, 158, 5200–
5210.
(11) Bidere, N.; Briet, M.; Durrbach, A.; Dumont, C.; Feldmann, J.;
Charpentier, B.; de Saint-Basile, G.; Senik, A. Selective Inhibition
of Dipeptidyl Peptidase I, Not Caspases, Prevents the Partial
Processing of Procaspase-3 in CD3-activated Human CD8þ T
Lymphocytes. J. Biol. Chem. 2002, 277, 32339–32347.
(12) Pagano, M. B.; Bartoli, M. A.; Ennis, T. L.; Mao, D.; Simmons,
P. M.; Thompson, R. W.; Pham, C. T. N. Critical Role of
dipeptidyl peptidase I in neutrophil recruitment during the
development of experimental abdominal aortic aneurysms.
Proc. Natl. Acad. Sci. 2007, 104, 2855–2860.
(31) Latajka, R.; Jewginski, M.; Makowski, M.; Paweiczak, M.;
Huber, T.; Sewald, N.; Kafarski, P. Pentapeptides containing
two dehydrophenylalanine residues;Synthesis, structural
studies and evaluation of their activity towards cathepsin C.
J. Pept. Sci. 2008, 14, 1084–1095.
(13) Wolter, P. J; Pham, C. T. N.; Muilenburg, D. J.; Ley, T. J.
Dipetidyl peptidase I is essential for activation of mast cell
chymases, but not tryptases in mice. J. Biol. Chem. 2001, 276,
18551–18556.
(14) Pham, C. T.; Ley, T. Dipetidyl peptidase I is required for the
processing and activation of granzymes A and B in vivo. Proc.
Natl. Acad. Sci. 1999, 96, 8627–8632.
(15) Kim, S.; Nadel, J. A. Role of neutrophils in mucus hypersecre-
tion in COPD and implications for therapy. Treat. Respir. Med.
2004, 3, 147–159.
(16) Novartis. Organic compounds. WO2007045476, 2007.
(17) Turk, D.; Janjic, V.; Stern, I.; Podobnik, M.; Lamba, D.; Dahl,
S. W.; Lauritzen, C.; Pedersen, J.; Turk, V.; Turk., B. Structure of
human dipetidyl peptidase I (cathepsin C): Exclusion domain
added to an endopeptidase framework creates the machine
for activation of granular serine protease. EMBO J. 2001, 20,
6570–6582.
(32) Barrett, A. J.; Kembhavi, A. A.; Brown, M. A.; Kirshke, H.;
Knight, C. G.; Tamai, M.; Hanada, K. L-trans-Epoxysuccinyl-
leucylamido(4-guanidino)butane (E-64) and its analogues as
inhibitors of cysteine proteinases including cathepsins B, H
and L. Biochem. J. 1982, 201, 189–198.
(33) Deaton, D. N.; Hassell, A. M.; McFayden, R. B.; Miller, A. B.;
Miller, L. R.; Shewchuk, L. M.; Tavares, F. X.; Willard, D. H.,
Jr. Novel and Potent cyclic cyanamide-based cathespin
K inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 1815–
1919.
(34) Falgueyret, J.-P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.;
Aubin, Y.; Rydzewski, R. M.; Prasit, P.; Riendeau, D.; Rodan,
S. B.; Percival, N. D. Novel, Nonpeptidic Cyanamides as
Potent and Reversible Inhibitors of Human Cathepsins K
and L. J. Med. Chem. 2001, 44, 94–104.
(18) Laine, D. I.; Busch-Petersen, J. Inhibitors of Cathepsin C
(DPPI). Expert Rev. Ther. Pat. 2010, 20, 497–506.
(19) McDonald, K. J.; Zeitman, B. B.; Reilly, T. J.; Ellis, S. New
observations on the substrate specificity of cathepsin C
(dipeptidyl aminopeptidase I). J. Biol. Chem. 1969, 244,
2693–2709.
(20) McDonald, J. K.; Callahan, P. X.; Ellis, S. Preparation and
specificity of dipeptidyl aminopeptidase I. Methods Enzymol.
1972, 25, 272–281.
(21) Molgaard, A.; Arnau, J.; Lauritzen, C.; Larsen, S.; Petersen, G.;
Pedersen, J. The crystal structure of human dipeptidyl peptidase
I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2.
Biochem. J. 2007, 401, 645–650.
(35) Rydzewki, R. M.; Bryant, C.; Oballa, R.; Wesolowki, G.;
Rodan, S. B.; Bass, K. E.; Wong, D. H. Peptidic 1-Cyanopyrro-
lidines: Synthesis and SAR of a Series of Potent, Selec-
tive Cathepsin Inhibitors. Biol. Med. Chem. 2002, 10, 3277–
3284.
(36) Vasilja, O.; Reinheckel, T.; Peters, C.; Turk, D.; Turk, V.; Turk,
B. Emerging role of cysteine cathepsins in disease and
their potential as drug targets. Cur. Pharm. Des. 2007, 13,
387–403.
(22) Korver, G. E.; Kam, C-.M.; Powers, J. C.; Hudig, D. Dipeptide
vinyl sulfones suitable for intracellular inhibition of dipeptidyl
peptidase I. Int. J. Immunopharmacol. 2001, 1, 21–32.
(23) Kam, C-.M.; Gotz, M. G.; Koot, G.; McGuire, M.; Thiele, D.;
Hudig, D.; Powers, J. C. Design and evaluation of inhibitors for
dipeptidyl peptidase I (Cathepsin C). Arch. Biochem. Biophys.
2004, 427, 123–134.
(24) Thompson, S. A.; Andrews, P. R.; Hanzlik, R. P. Carboxyl-
Modified Amino Acids and Peptides as Protease Inhibitors.
J. Med. Chem. 1986, 29, 104–111 .
(25) Bondebjerg, J.; Fuglsang, H.; Rosendal Valeur, K.; Pedersen,
J.; Naerum, L. Dipeptidyl nitriles as human dipeptidyl pepti-
dase I inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 3614.
(26) Guay, D.; Beaulieu, C.; Reddy, J. T.; Zamboni, R.; Methot, N.;
Rubin, J.; Ethier, D.; Percival, D. M. Design and synthesis
of dipeptidyl nitriles as potent, selective, and reversible
r
2010 American Chemical Society
147
DOI: 10.1021/ml100212k ACS Med. Chem. Lett. 2011, 2, 142–147
|