The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K

Article abstract of DOI:10.1016/j.bmcl.2007.12.047

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.

Full text of DOI:10.1016/j.bmcl.2007.12.047

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 923–928
The discovery of odanacatib (MK-0822), a selective
inhibitor of cathepsin K
Jacques Yves Gauthier,a Nathalie Chauret,a Wanda Cromlish,a Sylvie Desmarais,a
Le T. Duong,b Jean-Pierre Falgueyret,a Donald B. Kimmel,b Sonia Lamontagne,a
a
a
a
a
a
´
´ ´
´
Serge Leger, Tammy LeRiche, Chun Sing Li, Frederic Masse, Daniel J. McKay,
Deborah A. Nicoll-Griffith,a Renata M. Oballa,a James T. Palmer,c M. David Percival,a
Denis Riendeau,a Joel Robichaud,a Gideon A. Rodan,b Sevgi B. Rodan,b Carmai Seto,a
a
a
c
b
´
Michel Therien, Vouy-Linh Truong, Michael C. Venuti, Gregg Wesolowski,
Robert N. Young,a Robert Zambonia and W. Cameron Blacka,*
aMerck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Que., Canada H9H 3L1
bDepartment of Bone Biology and Osteoporosis, Merck Research Laboratories, West Point, PA 19846, USA
cCelera Genomics, Inc., 180 Kimball Way, South San Francisco, CA 94080, USA
Received 8 November 2007; revised 17 December 2007; accepted 19 December 2007
Available online 15 January 2008
Dedicated to the memory of Dr. Gideon Rodan, deceased, January 1, 2006
Abstract—Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabil-
ities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a
long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib
and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective
Cat K inhibitors.
ꢀ 2008 Elsevier Ltd. All rights reserved.
O
H
Cathepsin K (Cat K) is a lysosomal cysteine protease
that is highly expressed in osteoclasts, the cells responsi-
ble for bone degradation during bone remodeling. Type
I collagen is a major component of bone and Cat K has
high collagenase activity, particularly at the acidic pH
that is required to dissolve the calcium hydroxyapatite
component of bone. Emerging evidence that Cat K is
the primary enzyme involved in osteoclastic bone
resorption has made it an important target for the treat-
ment of osteoporosis.1 Several studies have shown that
Cat K deficiency leads to an increase in bone mineral
density (BMD).2 Pharmacological studies of Cat K
inhibitors in rats3 and monkeys4 have shown reductions
in biochemical markers of bone resorption and
N
CN
N
balicatib
H
O
N
N
O
H
N
CN
N
L-006235
H
O
N
N
N
S
O
O
H
N
N
relacatib
H
O
O
N
S
N
O O
Me
CF3
H
L-873724
CN
N
N
H
O
Keywords: Cathepsin K; Cysteine protease; Odanacatib; MK-0822;
Osteoporosis.
MeO2S
Figure 1. Published Cat K inhibitors.
*
Corresponding author. Tel.: +1 514 428 3073; fax: +1 514 428
4900; e-mail: blackc@merck.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.12.047

924
J. Y. Gauthier et al. / Bioorg. Med. Chem. Lett. 18 (2008) 923–928
increased BMD. Recently, clinical data have been dis-
closed for the Cat K inhibitor balicatib (Fig. 1), demon-
strating a reduction of biochemical markers of bone
resorption and increases in BMD over 1 year of
treatment.5
concerns that this compound may not be suitable for
once-daily dosing in humans. Incubations in human
hepatocytes showed that the major route of metabolism
was hydroxylation on the methine of the leucine side
chain (1)13 as shown in Scheme 1. A minor pathway
leading to the hydrolysis of the P1 amide bond (2) was
also observed. Analysis of plasma from several species
showed several circulating metabolites. In particular,
the lactone 3 was found to be circulating at high levels
in rhesus monkey (10· L-873724 concentration at 8 h)
even though it was only a minor component in rat plas-
ma. To understand the potential relevance of this
metabolite to humans, a synthetic standard of 3 was
incubated in fresh plasma from rat, rhesus monkey,
and human. In all three species, the lactone hydrolyzed
to hydroxyacid 4 over the course of the incubation
(37 ꢁC, 1 h). However this hydrolysis was much more
efficient in rat plasma (50% conversion) than in rhesus
monkey plasma (5% conversion). The extent of hydroly-
sis in human plasma was intermediate (28–40% conver-
sion) leading us to conclude that this metabolite would
likely circulate in humans.
We have previously reported on our effort to identify
potent and selective inhibitors of Cat K.6 Our initial
proof-of-concept compound, L-006235, was highly
selective over cathepsins B, L, and S in enzyme assays
and had good pharmacokinetics.7 However more de-
tailed studies revealed that the selectivity profile ns
was severely eroded in more physiologically relevant
cell-based enzyme occupancy assays.8 The relevance of
these data was demonstrated in a Cat S-dependent B cell
line assay in which L-006235 blocked antigen presenta-
tion. This loss of selectivity in cell-based assays can be
explained by the lysosomotropic properties of these ba-
sic, lipophilic compounds. Since off-target cathepsins are
found in lysosomes (pH 4–5), the lysosomal accumula-
tion of a basic Cat K inhibitor results in an apparent in-
crease in potency on these anti-targets. High selectivity
will be important to the success of a development candi-
date, precluding the use of a basic moiety in inhibitor
design.
Further investigations revealed that the leucine hydroxyl-
ation occurred exclusively due to CYP3A activity. Add-
ing the CYP3A inhibitor ketoconazole to the
hepatocyte incubations resulted in a near-complete
blockade of metabolism. When L-873724 was incubated
for 1 h in pooled human microsomes, only a 10% recov-
ery of the parent drug was observed. Microsomal incuba-
tion in the presence of a CYP3A inhibitory antibody gave
>90% recovery of parent drug. Finally, incubation with
several recombinant CYPs (1A1, 2D6*1, 3A4, 2C9*1,
2C9*2, 2C9*3, and 2C19) showed that only CYP3A led
to detectable metabolite formation. Metabolism by only
CYP3A can lead to variable exposure when co-dosed
with other drugs that are CYP3A inhibitors and inducers.
Balicatib is structurally related to L-006235 and is also
lysosomotropic.8 Whole cell assays showed poor selec-
tivity as was observed for L-006235. Recently it was an-
nounced that the Phase II development of balicatib has
been discontinued due to skin rash and rarer incidences
of morphea-like skin changes.9 Another Cat K inhibitor
in clinical development, relacatib, is non-basic and
therefore not lysosomotropic, but has poor selectivity
over cathepsins B, L, S, and V in enzyme assays.10
Our initial attempts to remove the basic substituent in
P3 led to Cat K inhibitors with poor activity, selectivity,
and pharmacokinetic properties. The loss in activity was
attributed to the loss of a beneficial ionic interaction be-
tween the charged amine and Asp61 in the S3 pocket.7
Since this residue is absent in the off-target cathepsins,
the potencies against the anti-targets were not dramati-
cally affected and selectivity was consequently reduced.
Replacing the P2 amide bond with a trifluoroethylamine
provided a 10- to 20-fold increase in potency on Cat
K.11 Using this motif, neutral inhibitors with high po-
tency and selectivity were prepared. L-873724 was iden-
tified as a 0.2 nM Cat K inhibitor with >800-fold
selectivity over other cathepsins. In vivo studies showed
that this neutral Cat K inhibitor suppressed biochemical
markers of bone resorption in a rhesus monkey model.12
To address the metabolic liabilities listed above, both
the P1 and P2 residues were modified to minimize leu-
cine hydroxylation, amide hydrolysis, and lactonization
(Table 1). Most P1 substituents resulted in a loss of
activity. One of the more active compounds (14) was
provided by incorporation of an (S)-benzyl group, but
the corresponding increase in potency on cathepsins B,
L, and S resulted in a poor selectivity profile. The (R)-
L-873724
OH
CF3
CF3
H
N
OH
CN
N
H
N
H
O
O
MeSO2
2
MeSO2
MeSO2
2
L-873724 has metabolic liabilities that prevented its fur-
ther development. An analysis of its metabolic profile
provided guidance for addressing these liabilities. Subse-
quent blocking of the key metabolic sites resulted in the
identification of odanacatib (MK-0822) which is cur-
rently in clinical development.
2
1
OH
OH
CF3
CF3
O
N
H
N
H
O
O
MeSO2
2
2
3
4
The pharmacokinetics of L-873724 in rat, dog, and
monkey have been reported.12 The short half-life (2 h)
and clearance (Cl = 7.5 mL/min/kg) in monkey raised
Scheme 1. Metabolic pathways for L-873724 based on in vitro and
in vivo studies.

J. Y. Gauthier et al. / Bioorg. Med. Chem. Lett. 18 (2008) 923–928
925
Table 1. In vitro activity of L-873724 analogues with P1 substitution and stabilized P2 groups
CF3 R1
H
N
CN
N
R2 R2
H
O
MeO2S
R2
a
IC50 (nM)
Compound
R1
Cat Kb
Cat B
Cat L
Cat S
L-873724
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
H, H
0.2
1.2
0.6
0.6
5.1
4.0
0.3
16
5239
264
178
2237
217
38
12
13
14
15
16
17
18
(S)-Me, H
(R/S)-Ph, H
(S)-Bn, H
(R)-Bn, H
1,1-Me2
>10,000
3453
953
3389
667
67
>10,000
>10,000
>10,000
>10,000
2940
>10,000
456
2834
2489
266
1,1-cPr
1,1-cBu
>10,000
>10,000
CF3
CF3
19
20
1,1-cPr
1,1-cPr
0.3
0.4
>10,000
>10,000
262
56
2650
170
F
F
21
22
1,1-cPr
1,1-cPr
0.2
100
472
110
17
15
Cl
<0.2
1528
Cl
F
F
F
23
1,1-cPr
1,1-cPr
1.5
0.2
434
750
89
60
F
24 (odanacatib)
1034
2995
a IC50 values represent an average of at least three titrations. Standard deviations for these assays were typically within 35% of the IC50 values.
b Humanized rabbit Cat K (Ref. 6); others are human enzymes. See Ref. 17 for assay conditions.
benzyl group provided a compound (15) that is 8-fold
less potent, suggesting that there is limited space for sub-
stituents in the back of the P1 pocket. The gem-dimethyl
substituted 16 shows similar behavior. The optimal sub-
stituent was a 1,1-cyclopropane ring (17) which gave an
in vitro profile similar to that of the unsubstituted ami-
nonitrile. Increasing the ring size to a 1,1-cyclobutane
substituent (18) resulted in a 50-fold loss in potency,
again demonstrating the restrictions of the P1 pocket.
differences of the resulting inhibitors are subtle, the im-
pact on both Cat K potency and selectivity is significant
(Table 1). For example, the two diastereomers 19 and
20, while having similar potency on Cat K, show a 10-
fold difference in Cat L potency. The difluoropropyl side
chain 21 has similar potency on Cat K, but has poor
selectivity on Cat B, L, and S. The dichloroethyl side
chain 22 has increased potency against all the tested
cathepsins, while the trifluoroethyl derivative 23 loses
activity on Cat K, but gains activity on Cat B. The opti-
mal combination of potency and selectivity was found
with the 4-fluoroleucine derivative 24 (odanacatib,
MK-0822). It was particularly gratifying to note that
this compound had little activity on Cat L, since the
Cat LÀ/À mouse shows several undesirable pheno-
types.14 Evaluation against other cathepsins gave IC50s
of 795 nM versus Cat F and 762 nM versus Cat V. There
Previous SAR studies of cathepsin inhibitors have
shown that the P2 substituent is critical to achieving
both potency and selectivity.7 For Cat K, an isobutyl
substituent in P2 has been found to provide an optimal
in vitro profile. The metabolic liability of this group led
us to attempt metabolic stabilization by introducing
halogens in various locations. Even though the steric

926
J. Y. Gauthier et al. / Bioorg. Med. Chem. Lett. 18 (2008) 923–928
was no measurable activity versus cathepsins C, H, and
Z (>10 lM). Odanacatib is a reversible inhibitor of Cat
K with on- and off-rates of 5.3 · 106 MÀ1 sÀ1 and
0.0008 sÀ1 (t1/2 ꢀ 14 min), respectively.
itors are less potent on rabbit Cat K than on human Cat
K, a ‘corrected bone res’ value has been calculated based
on the difference between the rabbit and human
potencies (Table 2). This allows comparisons of func-
tional potency to be made between compounds in a
human context. Odanacatib showed potency similar to
L-873724 and was 3- to 4-fold more potent than balica-
tib and relacatib. The reduced potency of inhibitors in
this assay relative to the Cat K enzyme assay may reflect
the high fractional inhibition of Cat K required to inhi-
bit bone resorption in osteoclasts.
The inhibitors described above were prepared according
to methods analogous to those published previously.12
The route is exemplified by the synthesis of odanacatib
(24) in Scheme 2. The synthesis of 4-fluoroleucinol be-
gins with commercially available aspartic acid derivative
5. Reduction of the acid followed by activation with to-
sic anhydride provides the cyclic carbamate 6. Methyl
Grignard addition to the benzyl ester and fluorination
of the resulting tertiary alcohol gave fluoride 7. Carba-
mate hydrolysis with barium hydroxide proceeded in
quantitative yield and the resulting amino alcohol was
silylated to facilitate isolation and provide stereochemi-
cal control in the subsequent imine addition step. Con-
densation of 8 with trifluoroacetaldehyde hemiacetal
provided imine 9 which was treated with bromophenylli-
thium to give the trifluoroethylamine in a 10:1 ratio of
S,S to R,S diastereomers. Desilylation followed by peri-
odic acid oxidation15 under anhydrous conditions gave
the carboxylic acid which was crystallized as the dicyclo-
hexylamine salt to give >99% de. Amide formation with
cyclopropaneaminoacetonitrile proceeded using HATU
to provide 11. Suzuki coupling followed by sulfide oxi-
dation then provided odanacatib 24. The P2 amino acids
and aminoalcohols required for analogues 19–23 were
prepared according to literature methods and converted
into final products as described in Scheme 2. Details are
provided in Supplementary material. Additional syn-
thetic routes to this class of compounds have been
reported.16
Odanacatib was evaluated in whole cell enzyme occu-
pancy assays using human HepG2 cells (Cat B, L) and
Ramos cells (Cat S) for selectivity versus off-target
cathepsins (Table 3) as previously described.17 In these
whole cell assays, odanacatib showed similar potencies
to those obtained in the corresponding purified enzyme
assays. This provided a high degree of selectivity versus
the corrected bone res Cat K assay, particularly com-
pared to the other catibs. The lowest selectivity of odan-
acatib is against Cat S, so its potential to inhibit Cat S
in vitro was addressed with two functional assays.
Odanacatib was a weak inhibitor of antigen presenta-
tion, measured in a mouse B cell line (IC50 = 1.5
0.4 lM), compared to the Cat S inhibitor LHVS
(IC50 = 0.001 lM) in the same assay.8 Odanacatib also
showed weak inhibition of the processing of the MHC
II invariant chain protein Iip10 in mouse splenocytes
compared to LHVS (minimum inhibitory concentration
1–10 lM versus 0.01 lM, respectively).18 The potency of
odanacatib is 4-fold greater against isolated mouse Cat
S than human Cat S, therefore the potential for Cat S
mediated immunosuppression appears to be low.
The potency of odanacatib was evaluated in a functional
bone resorption assay using rabbit osteoclasts cultured
on bovine bone. Since the majority of our Cat K inhib-
Cathepsins B, K, L, S, and V are all expressed in skin
tissue and have some ability to degrade collagen and
Table 2. Cat K enzyme activity and functional bone resorption assay
F
Compound
IC50 (nM)
CO2Bn
CO2Bn
Human
Cat K
Rabbit
Cat K
Rabbit Bone
Resa
‘Corrected’
Bone Resc
a, b
c, d
e, f
HN
O
HN
O
O
BocHN CO2H
O
7
L-873724
Odanacatib
Balicatib
0.2
0.2
0.6
0.5b
0.8
1.0
2.7
0.5
13
23
1
6
3
5
5
6
F
F
F
97 13
15
22
15
CF3
g
h, i
Relacatib
2
OH
OTBS
OTBS
N
H
N
H2N
a IC50 values represent an average of at least three titrations SEM.
b Humanized rabbit Cat K.
c Bone res IC50 · hCat K IC50/rabCat K IC50
10
9
8
Br
Br
F3C
j, k
F
F
.
CF3
CF3
H
H
N
l, m
N
CN
CN
N
H
N
H
O
O
Table 3. Whole cell potency on cathepsins K, B, L, and S
24
odanacatib
11
Compound
IC50 (nM)
Enzyme occupancy
MeO2S
Cat K ‘Corrected’
Bone Res
Scheme 2. Reagents and conditions: (a) ClCOOiBu, NMM, NaBH4,
DME, 85%; (b) Ts2O, pyr, dichloroethane, 83%; (c) MeMgBr, toluene/
THF, 85%; (d) DAST, CH2Cl2, 60%; (e) Ba(OH)2, EtOH/H2O, 100%;
(f) TBSCl, Et3N; (g) CF3C(OH)OEt, PhH, 88% (two steps); (h)
BrPhLi, THF; (i) TBAF, THF, 75% (two steps); (j) H5IO6, CrO3,
CH3CN, 60%; (k) 1-amino-1-cyanocyclopropane hydrochloride,
i-Pr2NEt, HATU, DMF, 80%; (l) MeSPhB(OH)2, PdCl2dppf, Na2CO3,
DMF, 70%; (m) H2O2, Na2WO42H2O, Bu4NHSO4, EtOAc, 97%.
Cat B
Cat L
Cat S
(HepG2) (HepG2) (Ramos)
L-873724
Odanacatib
Balicatib
3
5
4807
1050
61
1221
4843
48
95
45
22
15
2900
8
Relacatib
14
2

J. Y. Gauthier et al. / Bioorg. Med. Chem. Lett. 18 (2008) 923–928
927
Table 4. Pharmacokinetics of odanacatib (0.5% methocel + 0.2% SDS
as oral vehicle)
extracellular matrix. A key pathway for collagen degra-
dation by fibroblasts involves MMP-dependent partial
digestion and phagocytosis, followed by cysteine
cathepsin-dependent intracellular degradation.19,20 We
hypothesized that the fibrotic events caused by balicatib9
are due to inhibition of multiple cathepsins by virtue of
its lysosomotropic nature, resulting in a build up of ma-
trix. A cellular model was used in which primary human
dermal fibroblasts (HDF) were cultured in 3-D collagen
gel and inhibitors added for the final 3 days.21 The cells
were removed from the collagen by collagenase treat-
ment, fixed and permeabilized, and intracellular type I
collagen detected using an anti-type I collagen mAb
and a FITC-labeled 2oAb with quantitation by flow
cytometry (see Supplementary material). Balicatib and
the non-selective cathepsin inhibitors relacatib (Fig. 2)
and E64/E64d (data not shown) caused a 3- to 7-fold
accumulation of intracellular Type I collagen in HDF
at concentrations of 1–10 lM. In contrast, an inactive
structural analogue of balicatib (compound 2 in Ref.
8) and an inactive diastereomer of relacatib (compound
13 in Ref. 10) showed less than 1.5-fold accumulation of
collagen at concentrations up to 10 lM (data not
shown). The high degree of cellular selectivity of odan-
acatib was again demonstrated by its minimal effect on
collagen accumulation, even at the relatively high con-
centration of 10 lM (Fig. 2).
Species
po Dose %F Cl Half-life Vdss
(mg/kg) (mL/min/kg) (h) (L/kg)
Rat
Dog
10
5
8
6
7
2.0
6
57
18
1.1
0.6
1.6
0.13
6.1
Rh. Monk.
5
bioavailability was found to be highly dependent on
vehicle, dosage, and sample preparation. For example,
in the dog, the oral bioavailability when dosed as a sus-
pension in 0.5% methocel was only 6% at 5 mg/kg, but
increased to 100% when dosed as an amorphous disper-
sion prepared by adding a PEG-200 solution of the com-
pound to methocel with sonication. Similarly, the
bioavailability in rats when dosed at 5 mg/kg as a solu-
tion in PEG-400 was found to be 38%. The half-lives
were long in all species and were consistent with the ob-
served metabolic stability.
In conclusion, by blocking the sites of metabolism on L-
873724, a compound was identified with minimal
in vitro metabolism and long half-lives in preclinical spe-
cies. Odanacatib has greater bone resorption activity
and greater selectivity versus off-target cathepsins than
do balicatib and relacatib. This reduced activity against
other cathepsins may be responsible for the lower level
of undesired collagen accumulation in skin fibroblasts
compared to balicatib and relacatib. Odanacatib is cur-
rently in clinical development for the treatment of post-
menopausal osteoporosis.
Odanacatib exhibited excellent metabolic stability in
hepatocyte incubations across several species. In stan-
dard incubations (2 · 106 cells/mL, 20 lM, 2 h), a 96%
recovery of parent was found in rat hepatocytes and a
98% recovery was obtained in rhesus monkey hepato-
cytes. High recovery (>99%) was observed in both dog
and human hepatocyte incubations.
Supplementary data
The pharmacokinetics of odanacatib were evaluated in
several preclinical species (Table 4). This molecule is
highly crystalline with low aqueous solubility, and oral
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.
2007.12.047.
References and notes
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0.01
0.1
1
10
Inhibitor Concentration (µM)
Figure 2. Effect of balicatib, relacatib, and odanacatib on the
intracellular accumulation of Type I collagen in cultured primary
human dermal fibroblasts. The data represent the average SD for at
least n = 2 experiments for each inhibitor. A similar profile was
observed using cells from a second donor.

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