Discovery of cathepsin S inhibitor LY3000328 for the treatment of abdominal aortic aneurysm

Article abstract of DOI:10.1021/ml500283g

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

Full text of DOI:10.1021/ml500283g

Letter
pubs.acs.org/acsmedchemlett
Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of
Abdominal Aortic Aneurysm
Prabhakar K. Jadhav,* Matthew A. Schiffler, Kostas Gavardinas, Euibong J. Kim, Donald P. Matthews,
Michael A. Staszak, D. Scott Coffey, Bruce W. Shaw, Kenneth C. Cassidy, Richard A. Brier, Yuke Zhang,
Robert M. Christie, William F. Matter, Keyun Qing, Jim D. Durbin, Yong Wang, and Gary G. Deng
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
S
* Supporting Information
ABSTRACT: Cathepsin S (Cat S) plays an important role in
many pathological conditions, including abdominal aortic
aneurysm (AAA). Inhibition of Cat S may provide a new
treatment for AAA. To date, several classes of Cat S inhibitors
have been reported, many of which form covalent interactions
with the active site Cys25. Herein, we report the discovery of a
novel series of noncovalent inhibitors of Cat S through a
medium-throughput focused cassette screen and the optimiza-
tion of the resulting hits. Structure-based optimization efforts
led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds
binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and
efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
KEYWORDS: Cathepsin, abdominal aortic aneurysm, development candidate, noncovalent
pH optimum is between 6.0 and 7.5, and the enzyme is active
outside the lysosome.
bdominal aortic aneurysm (AAA) is a frequently fatal age-
Arelated disease in which the abdominal aorta, often
between the renal and iliac arteries, enlarges and eventually
ruptures. The risk of rupture increases with increase in aortic
diameter, particularly with a diameter larger than 5.5 cm. The
prevalence of AAA in patients over the age of 60 years is 4−8%
and 0.5−1.5%, in men and women, respectively.1−7 The most
frequently recognized risk factors for AAA are advanced age,
history of cigarette smoking, male gender, and family history.
AAA is typically asymptomatic, so early detection is a challenge.
Between rupture and postsurgical complications, AAA is
responsible for at least 15,000 deaths annually in the USA.
There are no approved drugs for the treatment of AAA; the
only options for AAA patients are open surgery and
endovascular stents. Patients are eligible for surgery when the
abdominal aorta reaches a diameter of 5.5 cm because the risk−
benefit balance is not in favor of intervention below this
threshold. Thus, AAA patients with an aortic diameter of less
than 5.5 cm have no viable treatment options.
Cat S is a 225 amino acid, 24.8 kDa lysosomal cysteine
protease that belongs to the papain superfamily of proteases.8
Cat S controls MHC class II-mediated antigen presentation by
epithelial cells.9 Immune cells such as macrophages and
microglia secrete Cat S in response to inflammatory mediators
such as lipopolysaccharides, proinflammatory cytokines, and
neutrophils. Cat S is expressed by antigen-presenting cells
including macrophages, B-lymphocytes, dendritic, microglia,
and some epithelial cells. Although many lysosomal proteases
function only under acidic conditions, Cat S is an exception; its
In a 28 day chronic angiotensin II infusion model of AAA
with apolipoprotein E (ApoE) deficient (ApoE−/−) mice and
ApoE/Cat S double-knockout (ApoE−/−Cat S−/−) mice, AAA
lesions were analyzed.10 It was found that Cat S expression
increased significantly in mouse AAA lesions. The AAA
incidence in ApoE−/−Cat S−/− mice was much lower than
that in ApoE−/−Cat S+/+ mice (10% vs 80%). There was
significant reduction in external and luminal abdominal aortic
diameters, medial elastin fragmentation, and adventitial
collagen in the double knockout mice. Cat S deficiency
reduced AAA lesion media smooth muscle cell (SMC)
apoptosis, adventitial microvessel content, and inflammatory
cell accumulation. Cat S also has been shown to play important
roles in autoimmune disorders and inhibition of Cat S enzyme
activity in such pathological conditions might have therapeutic
value.11
In Cat S, it is known that Cys25 is capable of forming a
reversible or irreversible covalent bond with electrophilic
centers, so several classes of inhibitors reported in the literature
contain electrophiles.12,13 Representative examples of Cat S
inhibitors from the literature (Chart 1) contain different
electrophilic groups, which are capable of forming this bond.
For example, 114 is a Michael acceptor, whereas 215 contains a
Received: July 10, 2014
Accepted: August 27, 2014
Published: August 27, 2014
© 2014 American Chemical Society
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Chart 1. Selected Cathepsin S Inhibitors
Table 1. hCat S and mCat S Inhibition Data
compd
hCat S IC50 (nM)
mCat S IC50 (nM)
6
7
8
9
5
1170 227 (n = 7)
1290 453 (n = 6)
4000 1630 (n = 4)
12.4 6.48 (n = 10)
7.70 5.85 (n = 11)
1570 108 (n = 3)
2780 230 (n = 3)
3930 553 (n = 3)
3.91 0.71 (n = 8)
1.67 1.17 (n = 9)
The series of compounds disclosed in this publication are
inactive against rCat S due to a G137C mutation.21 This
mutation reduces the size of the S2 pocket, thereby rejecting
the binding of Cat S inhibitors with larger P2 groups.
After a medium-throughput screen of a structurally diverse
cassette of approximately 120,000 compounds, several actives
were identified. We focused our attention on nonpeptidic
compound 622 (Chart 2) with a Cat S IC50 of 1.3 μM (Table 1)
and selectivity against human cathepsin L (Cat L IC50 of >100
μM). The amidine in 6 was judged undesirable for a drug-like
molecule, so it was readily replaced with a urea linker to
provide 7, with no loss of potency. From what was previously
known about Cat S inhibitors, we were unable to predict a
reasonable binding mode for 7. Consequently, there was
impetus to understand how 7 interacted with the enzyme. The
3-dimensional (3D) structure of the Cat S-7 complex was
resolved by protein X-ray crystallography at a 1.8 Å resolution
and R factors of 0.185 (working) and 0.210 (free). The 3D
structure of the complex (Figure 1A) revealed a novel binding
mode in which the phenyl ring of the benzamide occupied the
S3 binding pocket and formed a face-to-edge interaction with
Phe70. In addition, the phenyl moiety of the benzamide formed
a π-stacking interaction with the peptide bond between Gly68
and Gly69. The aryl ring of the tetrahydronaphthalene
substructure occupied the S2 pocket and formed a face-to-
edge interaction with Phe70. The N-methylpiperazine was
partly in proximity with Phe211 and partly outside the S2
subsite. There was only one apparent electrostatic interaction
observed between 7 and Cat S: the NH residue of the
benzamide formed a strong hydrogen bond (3 Å) with the
carbonyl oxygen of the Gly69. It was noteworthy that the active
site Cys25 residue did not make any contact with the inhibitor;
the closest non-hydrogen atom of 7 was at a distance of 4.3 Å
from the sulfur of Cys25.
cyclic ketone. Similarly, 313 contains an α-ketoamide as an
electrophilic center, and 416 contains a nitrile, which is capable
of forming a thioimidate with Cys25. Compound 3 is a very
potent inhibitor of Cat S, but it is also a very potent inhibitor of
cathepsins L, V, and B. In some cases, the reactive nature of the
inhibitors creates challenges in optimization of selectivity
during lead optimization. Nonspecific reactivity with off-target
biomolecules can potentially contribute to toxicity for
molecules containing electrophilic centers. There are reports
on noncovalent Cat S inhibitors that do not interact with the
active site Cys25.17 We set out likewise to identify Cat S
inhibitors that lack an electrophilic center and do not form
covalent bond with active site Cys25. Herein, we report the
structure of noncovalent Cat S inhibitor 5 (Chart 2), which
Chart 2. Structures of Nonpeptidic, Noncovalent, Selective
Cat S Inhibitors
The availability of the 3D protein crystal structure of the Cat
S-7 complex opened the door for structure-based drug design.
With this structure in hand, we turned our focus toward the
optimization of the potency, selectivity, drug disposition,
biopharmaceutical, and toxicological properties. The structure
suggested that the urea linker between the tetralin and the N-
methylpiperazine served little purpose in contributing to
electrostatic interactions. Indeed, compound 8 has comparable
potency to 7. The purpose of linking N-methylpiperazine
directly to phenyl ring in 8 was to improve solubility properties
of 8 over 7. Further examination of the 3D structure of the Cat
S-7 complex revealed that the NH residue of Gly69, usually
forming a H-bond with the amide carbonyl of a P1 group, had
no complementary hydrogen bond acceptors from 7. We
hypothesized that placing an O-linked carbamate group on the
homobenzylic carbon might provide a hydrogen bond acceptor
complementary to the NH of Gly69. In addition, we posited
that replacing the N-methyl group of the piperazine in 8 with a
3-oxetanyl group would reduce the pKa of the distal piperazine
nitrogen while lowering the overall lipophilicity of the target
does not form covalent bond with Cys25 and occupies the S2
and S3 pockets of the Cat S enzyme. Inhibitor 5 has potency,
selectivity, drug disposition, toxicology, physicochemical, and in
vivo properties suitable for clinical development.
Test compounds were evaluated for their activity in Cat S
and mCat S enzyme inhibition assays (Table 1).18,19 Similarly,
selectivity against other cysteine proteases such as Cat L, Cat K,
Cat B, and Cat V was determined in enzyme inhibition assays
where compounds 5−9 exhibited very high selectivity.20
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interaction between the piperazine moiety and Phe211 side
chain.
Compounds 5 and 9 were found to have desirable
physicochemical properties (Table 2). Preclinical pharmacoki-
netic evaluation of 5 and 9 demonstrated that both compounds
had a similar profile in dog.20 However, compared to 9, the
clearance of 5 was 3-fold lower, and the exposure was 3-fold
higher in rat. In dog, both compounds were highly bioavailable
(F > 75%), possessed low clearance (CL < 4 mL/min/kg), low
volume of distribution (Vd < 1 L/kg), and relatively short half-
lives. Additionally, 5 and 9 showed low in vitro CYP450
inhibition (<15% at 10 μM for CYP3A4, CYP2D6, and
CYP2C9); low in vitro metabolism in mouse, rat, dog, and
human liver microsomes (<20% after 30 min incubation at 4
μM); and good permeability (MDCK A-B > 4%). At a 100 μM
concentration of 5 there was only 6% displacement of [3H]-
astemizole in an assay with HEK293 membrane preparation,
indicating low potential of hERG blockade. Also, when
incubated in human or rat plasma for up to 30 min, there
was no statistically significant loss of parent compound.
The in vivo efficacies of 5 and 9 were studied in a mouse
model of AAA (Figure 2). In this model, inflammation was
induced using CaCl2 applied to the ablumenal surface. It was
shown that features of the disease state in this model resemble
those of human AAA.23 Both compounds exhibited a dose-
responsive aortic diameter reduction at 1, 3, 10, and 30 mg/kg.
However, 9 had a less profound effect than did 5. At the lowest
dose of 1 mg/kg of 5, the aortic diameter was reduced by 58%,
Figure 1. Ribbon figure of (A) Cat S (yellow) in complex with 7
(cyan) and (B) Cat S (cyan) in complex with 5 (yellow).
compound 9. Indeed, we found 9 to be about 300-fold more
potent than 8. The benzylic carbon in 9 was replaced with
oxygen to provide 5 with reduced potential for metabolic
oxidation. Compound 5 maintained excellent in vitro potency
and selectivity. Compared to 7, the protein−crystal structure of
the Cat S-5 complex (Figure 1B) revealed that 5 not only
maintains the hydrogen bond between the NH of the
benzamide and the carbonyl oxygen of the Gly69 residue
(2.8 Å), but also makes two additional hydrogen bonds with
Cat S. The carbonyl oxygen of the carbamate group of 5
formed a hydrogen bond (3.1 Å) with the NH of Gly69, and
the NH of the carbamate group formed a hydrogen bond (2.9
Å) with the backbone carbonyl group of Asn163. While the
structures of 5 and 7 were nearly identical, there were some
subtle differences in relative positioning between them. For
example, the oxygen atom in the chromane moiety of 5 was
closer to the sulfur atom of Met71 at 3.3 Å than the
corresponding distance of 3.9 Å for the benzylic carbon of 7.
This S−O distance was near the sum of their van der Waals
radii, and its geometry reflects a possible orbital overlap. Also, 5
had a basic nitrogen atom located 4.9 Å from the center of
phenyl ring of Phe211 indicating a possible cation−π
Figure 2. Effect of Cat S inhibitors 9 (A) and 5 (B) following 28 days
of oral, BID dosing in mouse CaCl2 AAA model.
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Table 2. Physicochemical Properties of 5 and 9
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ment.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data for the preparation
of compounds 5−9, in vitro ADME data for 5 and 9, and
preclinical in vivo ADME data for 5 and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
Accession Codes
Coordinates and structure factors are available from the Protein
Data Bank with accession codes 4P6G and 4P6E for Cat S/5
and Cat S/7 binary complexes, respectively.
AUTHOR INFORMATION
Corresponding Author
*(P.K.J.) Tel: +1 317 433 1535. Fax: +1 317 277 3652. E-mail:
jadhav_prabhakar@lilly.com.
■
Funding
Use of the Advanced Photon Source, an Office of Science User
Facility operated for the U.S. Department of Energy (DOE)
Office of Science by Argonne National Laboratory, was
supported by the U.S. DOE under Contract No. DE-AC02-
06CH11357. Use of the Lilly Research Laboratories Collabo-
rative Access Team (LRL-CAT) beamline at Sector 31 of the
Advanced Photon Source was provided by Eli Lilly Company,
which operates the facility.
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Notes
The authors declare no competing financial interest.
ABBREVIATIONS
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AAA, abdominal aortic aneurysm; BID, twice daily; Cat B,
human cathepsin B; Cat K, human cathepsin K; Cat L, human
cathepsin L; Cat S, human cathepsin S; Cat V, human cathepsin
V; CD4, cluster of differentiation 4; compd, compound;
CYP450, cytochrome P450; mCat S, mouse cathepsin S; PO,
by mouth; rCat S, rat cathepsin S; SGF, simulated gastric fluid
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Letter
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