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Discovery and development of odanacatib: A selective cathepsin K inhibitor for the treatment of osteoporosis
Discovery and development of Discovery and development of odanacatib:odanacatib: A selective cathepsin K A selective cathepsin K inhibitor for the treatment of inhibitor for the treatment of osteoporosisosteoporosis
Shawn J. StachelOn behalf of the odanacatib discovery and product development teamsMerck Research Laboratories
8th RSC-SCI Symposium on Proteinase Inhibitor Design
April 16, 2013
2
AcknowledgementsAcknowledgementsBiologyChristine BrideauWanda CromlishSylvie DesmaraisJean-Pierre FalgueyretLouis-Jacques FortinSonia LamontagneFrance LandryFrederic MasseDave PercivalDenis RiendeauPaul TawaJennifer WangComp. Med.Stephanie AlleynLiette BelairJoel BosquetCarl BrièreNancy KellyGayle LapointeMira LavoieSonia LesvesqueDenis NormandinKaren OrtegaRoberta RasoriJosianne RozonWayne Sturkenboom Simon Wong
ChemistryKevin BatemanChristopher BaylyCameron BlackMichael BoydNathalie ChauretSheldon CraneStephen DayJacques Yves GauthierRobert HouleElise IsabelC.K. LauSerge LegerTammy LeRicheJean-Francois LevesqueChun-Sing LiChristophe MellonRenata OballaJoel RobichaudBruno RoyJohn ScheigetzCarmai SetoMichel TherienLaird TrimbleJean-Francois TruchonVouy-Linh TruongQingping Wang
Bone Biology (WP)Don KimmelSevgi RodanGideon RodanLe DuongPat MasarachiaBrenda PennypackerMaureen PickarskiGregg WesolowskiYa ZhuoPharmaceutical R&DCynthia BazinSophie-Dorothee ClasElizabeth KwongPauline LukRafik NaccacheWayne ParentSuzanne SpagnoliDendi SusantoHongshi YuSafety AssessmentLaura GumprechtCindy FishmanPharmacologySylvie Toulmond
Celera
Process ChemistryPaul O’SheaDean BenderMirlinda BibaJennifer ChilenskiJimmy DaSilvaRich DesmondPaul DevinePete DormerBruce FosterDon GuathierDanny GauvreauFrancis GosselinDerek HendersonGreg HughesJohn LeazerBill LeonardJohn LimantoChristian NadeauThorsten RosnerKara RubinAli ShafieeVeena UpadhyayChris WelchClinical DevelopmentAubrey Stoch Tony LombardiDeborah Miller Albert Leung
3
Osteoporosis: A Continuing Disease BurdenOsteoporosis: A Continuing Disease Burden
Estimated 200 million women worldwide with osteoporosis.1
Only ~20% of osteoporosis patients are currently treated Hip fractures cause high morbidity and mortality2
− ~20% die in the 1st year− ~33% are totally dependent or in a nursing home after one year
1 Kanis JA (2007) WHO Technical Report, University of Sheffield, UK: 662 International Osteoporosis Foundation statistics.
From the International Osteoporosis Foundation
Osteoporosis: “porous bones” A progressive bone disease characterized by decreased bone density
and mass. Leads to an increased risk of fracture
Trabecular bone deteriorated
Normal Osteoporosis
4
Bone RemodelingBone Remodeling
Healthy: Bone resorption = formationOsteoporosis: Bone resorption > formation
5Rodan & Duong Bone Key 2008, 5, 6
Collagen
Electron micrograph of an osteoclast on bone
Osteoclast – The Target Cell for Cathepsin K InhibitionOsteoclast Osteoclast –– The Target Cell for Cathepsin K InhibitionThe Target Cell for Cathepsin K Inhibition
N
N
Cathepsin KpH=5
Trans- endocytosis
Lysosomes
SealingZone
Bone resorption by osteoclasts is the initial step in remodeling
6
Cathepsin K Deficiency Cathepsin K Deficiency Cathepsin K Deficiency Discovered in 19951
– Highly expressed in osteoclast– Cleaves at multiple sites in triple helical region of
collagen type I and II
Pycnodysostosis is a genetic disease associated with cathepsin K deficiency2,3
– Rare autosomal recessive skeletal dysplasia– ~150 cases reported worldwide – Short stature with high bone mass and increased
fragility associated with high risk of fracture– Normal intelligence, sexual development and
lifespan
Cat K null mice4
– Osteopetrotic phenotype– Increased bone density – Otherwise healthy and fertile
1 Inaoka, et al, BBRC 1995, 206, 892 Schilling, et al, Osteoporosis Int 2007, 18, 6593 Saftig PNAS 1998, 95, 13453.4 Gelb, et al, Science 1996, 273, 1236
Henri de Toulouse-Lautrec
7
Cathepsin K as a Therapeutic TargetCathepsin K as a Therapeutic TargetCathepsin K as a Therapeutic Target
Data suggestive that cathepsin K represents a promising target for treatment of osteoporosis
– Human and mouse genetic data – Cathepsin K collagenase activity– Restricted cellular distribution
Goal: To develop an orally active, selective and reversible cathepsin K inhibitor for treatment of osteoporosis
8
Substrate to Inhibitor: WarheadSubstrate to Inhibitor: WarheadSubstrate to Inhibitor: Warhead
Use knowledge of mechanism to convert substrate into inhibitor:
R
O
NR'
HS-Enz
H
R
HO
N R'
H
+ Enz-SHH2O
Acyl enzymeintermediate
Tetrahedral intermediate
S-Enz
R
O
S-EnzR
O
OH
- H2N-R'
Replace scissile bond with an electrophile (warhead) that reacts with active site cysteine:
Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Brömme, D. J. Med. Chem. 1995, 38, 3193
9
Substrate to Inhibitor: Recognition SequenceSubstrate to Inhibitor: Recognition Sequence
Cathepsin K cleaves Type I collagen at multiple positions Recognition sequence1: Gly-Leu-Lys—Gly-His
Recognition sequence combined with electrophilic warhead gives a mechanism based-inhibitor of cathepsin K2,3
1Atley, M.; Mort, J. S.; Lalumiere, M.; Eyre, D. R. Bone 2000, 26, 2412McGrath, M. E.; Klaus, J. L; Barnes, M. G.; Brömme, D. Nat. Struct. Biol. 1997, 4, 1053Brömme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T Biochem. J. 1996, 315, 85
P3 P2 P1 P1’ P2’
APC3328
NH O
HN S
O OO
NHN
P1
P3
P2
NH O
HN
O
NH2
HN
O
NH
HN
O
N N
P1
P3
P2
P1'
P2'
10
Opportunities for Inhibitor DesignOpportunities for Inhibitor DesignOpportunities for Inhibitor Design• Co-crystal reveals key interactions with cathepsin K and opportunities
for obtaining selectivity
McGrath, M. E.; Klaus, J. L; Barnes, M. G.; Brömme, D Nat. Struct. Biol. 1997, 4, 105
NH O
HN S
O OO
NHN
S2
S3
S1
– S2 pocket suggests accommodation of alternative hydrophobic groups– S3 sub-site contains aspartic acid (Asp61) that may be exploitable for
selectivity– P2-P1 amide forms key interaction with enzyme backbone (Gly66, Asn158)– P2-P3 amide: NH hydrogen-bond to Gly66, oxygen points towards solvent
– S1 pocket is a narrow groove on enzyme
11
Irreversible inhibitors have potential liabilities Vinyl sulfone can be replaced by nitrile (electrophilic)
– Adds cysteine reversibly to form thioimidate
Enz-SH
Nitrile-based inhibitor
Optimization to dipeptide nitrile
L-006235Cat K IC50 = 0.2 nM
Reversible InhibitorsReversible Inhibitors
J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520
HN S
O
OO
NH
O
N
HN
12
Selective Inhibition of Cathepsin K is Important to Avoid Potential Off-target ActivitySelective Inhibition of Cathepsin K is Important Selective Inhibition of Cathepsin K is Important to Avoid Potential Offto Avoid Potential Off--target Activitytarget Activity
Fifteen human cathepsins are present inside cells within acidic compartments called lysosomes Potential consequences of off-target inhibition
− Cat L: cardiomyopathy, impaired neovascularization− Cat F: neuronal ceroid lipofuscinosis− Cat S: impaired immune response
High selectivity for cathepsin K desired to avoid potential off-target effects
F. Lecaille Chem. Rev. 2002, 102, 4459.
Cathepsins
Cysteine CathepsinsB, C, F, H, K, L, O, S, V, W, Z
Aspartyl CathepsinsD, E
Serine CathepsinsA, G
13
L-006235 : A Potent, Selective, Reversible Dipeptidic Nitrile Inhibitor of Cathepsin KL-006235 : A Potent, Selective, Reversible Dipeptidic Nitrile Inhibitor of Cathepsin K
– >5000-fold selective in purified enzyme assays– Active in rabbit and monkey models of osteoporosis
IC50 (nM)Cat K
0.2
Cat B
1100
Cat L
6300
Cat S
47000
Cat F
3000
J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520
14
L-006235 in Cathepsin K LL--006235 in Cathepsin K 006235 in Cathepsin K
Asn166
Cys25
Asp61
Gly66
3.0
2.9
2.9
15
Loss of Specificity of Cathepsin K Inhibition: Whole Cell AssayLoss of Specificity of Cathepsin K Inhibition: Loss of Specificity of Cathepsin K Inhibition: Whole Cell AssayWhole Cell Assay
– High selectivity profile of L-006235 is lost in whole cell assays
Inhibition of Cathepsins, IC50 (nM)
Cathepsin SCathepsin LCathepsin BCathepsin K
0.2L-006235
Enzyme Enzyme Enzyme EnzymeCell Cell Cell
1100 17 6300 340 47000 790
Cell
5
L-006235
J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520
16
Hypothesis: Basic Inhibitors Accumulate in Acidic Lysosomes and Inhibit Off-Target Cathepsins
Hypothesis: Basic Inhibitors Accumulate in Acidic Lysosomes and Inhibit Off-Target Cathepsins Lysosomotropism: accumulation of lipophilic weak bases in acidic
sub-cellular compartments Lysosome
pH ~7
pH ~5BH+
B
Plasma Membrane
pH ~7B
MergedLL--006235006235
DNDDND--99 (lyso)99 (lyso)
Co-localization in live HUVECsL-006,235
weak basic amine
J. Falgueyret et. al. J. Med. Chem 2005, 48, 7535
17
Cat K Inhibitors in Whole Cell AssaysCat K Inhibitors in Whole Cell Assays
Inhibition of Cathepsins, IC50 (nM)
NH
ONH
O
N
SNN
N
L-006235 Cmpd 2
NH
ONH
O
N
SNO
NBasic Neutral
Cathepsin SCathepsin LCathepsin BCathepsin K
0.22.3
L-006235Cmpd 2
Enzyme Enzyme Enzyme EnzymeCell Cell Cell
11004200
17 630024000
340 4700027000
7902900 >10000 >10000
– Non-basic analogs show reduced activity in cell-based assays – Non-basic P3 groups are generally less active
J. Falgueyret et. al. J. Med. Chem 2005, 48, 7535
18
10- to 100-fold increase in intrinsic potency
Improved enzyme selectivity
Enhanced pharmacokinetics (bioavailability, half-life)
Liability of basic group: – Lysosomotropism leading to loss of functional selectivity
Why have a Basic Substituent?Why have a Basic Substituent?
19
SAR Optimization EffortsSAR Optimization EffortsSAR Optimization Efforts
NH O
HN
O
N
SNN
N
ON
N
O
N S
R S RHN
RO O
O
N N
O
Ar
CN
R
– Extensive SAR studies on dipeptide framework resulted in loss ofselectivity and/or potency
– Abandoned dipeptide series of inhibitors
20
Amide ReplacementAmide Replacement
Cat K = 56 nMCat L = 498 nM (9x)Cat S = 1578 nM (28x)Cat B = >10000 nM (>180)
HN CN
ONH
O
Cat K = 51 nMCat L = 42 nM (0.8x)Cat S = 41 nM (0.8x)Cat B = 1903 nM (37x)
Increase in
selectivity
Amide bond can be replaced but loss in Cat K potency Selectivity can still be achieved without P2-P3 amide
Cat K = 73 nMCat L = 3666 nM (50x)Cat S = 3401 nM (46x)Cat B = >10000 nM (137x)
Loss of
selectivity
J. Robichaud et. al. BMCL 2004, 14, 4291
P2-P1 amide forms key interaction with enzyme backbone (Gly66, Asn158)but, P2-P3 amide NH hydrogen-bond to Gly66, oxygen points towards solvent
21
Further Optimization of Amide ReplacementFurther Optimization of Amide Replacement
HN CN
O
NHN
(R)-2Cat K = 11 nMCat L = 3950 nM (359x)Cat S = 2010 nM (183x)Cat B = 3725 nM (339x)
Potency
selectivity
High selectivity can still be achieved without P2-P3 amide with addition of basic P3 group
Cat K = 56 nMCat L = 498 nM (9x)Cat S = 1578 nM (28x)Cat B = >10000 nM (>180)
J. Robichaud et. al. BMCL 2004, 14, 4291J. Robichaud et. al. J. Med. Chem. 2003, 46, 3709
22
ReRe--Addition of a HydrogenAddition of a Hydrogen--Bond DonorBond Donor
Additional of hydrogen bond donor is favorable for cat K potency.
X = Cat K (IC50)NH 54 nMO 1147 nMCH2 2353 nM
X = Cat K (IC50)NH 72 nMO 1475 nMCH2 3394 nM
X = Cat K (IC50)NH 208 nMO 2999 nMCH2 2349 nM
J. Robichaud et. al. BMCL 2004, 14, 4291
23
Potency and Selectivity OptimizationPotency and Selectivity Optimization
selectivity
Selectivity and potency can still be achieved without P2-P3 amide with addition of basic P3 group
Cat K = 3 nMCat L = 2101 nM (700x)Cat S = 158 nM (53x)Cat B = 1812 nM (604x)
Cat K = 2 nMCat L = 108 nM (54x)Cat S = 24 nM (12x)Cat B = 26 nM (13x)
HN CN
O
NHN
(R)-2
Cat K = 11 nMCat L = 3950 nM (359x)Cat S = 2010 nM (183x)Cat B = 3725 nM (339x)
J. Robichaud et. al. BMCL 2004, 14, 4291
24
Another PeptidomimeticAnother PeptidomimeticAnother Peptidomimetic
NH
HN
OCN
O
NS
NN
How can P2-amide be replaced while maintaining H-bond capability?
H-bond donor requires non-basic nitrogen– Non-basic amine (pKa = 1.5) is not protonated at physiological pH
Retains the H-bond donating properties of an amide bond
NH
O O
NHO
NH
CF3 O
NHO
M. Zanda et. al ChemMedChem 2007, 2,1693
25
NH O
HN CN
O
50
CFCF33 Amide Replacement: PAmide Replacement: P22 Leucine vs CyclohexylLeucine vs Cyclohexyl
Trifluoroethylamine is an effective amide isostere Cyclohexyl ring in P2 is much less potent than the isobutyl side-chain Modeling suggests loss of potency in cyclohexyl analog is a result of
steric interactions between P2 and the CF3 group
50
NH O
HN CN
O
W. C. Black et. al. BMCL 2005, 15, 4741Black, W. C.; Percival, M. D. ChemBioChem 2006, 7, 1525
26
CF3 Amide ReplacementCF3 Amide Replacement
Phenyl piperazine has greater potency and selectivity than thiazole piperazine
Can this exquiste potency/selectivity advantage be extended to non-basic inhibitors?
NH
CF3
O
HN CN
NHN
O
HN CNN
H
CF3
N
SNN
HN CN
ONH
O
N
SNN
0.03 3315 26 848
IC50 (nM)
Cat K Cat B Cat L Cat S
0.2L-006235
1100 6300 47000
0.005 1110 47 451
3
4
W. C. Black et. al. BMCL 2005, 15, 4741
27
C. S. Li et al. BMCL 1985,16, 1985
Non-basic derivatives in this series are potent and selective L-873724 stands out as best compound in this series
““NonNon--basicbasic”” PP33 SubstituentsSubstituents
L-873724
28
Why are Trifluoroethylamines so Potent?Why are Trifluoroethylamines so Potent?X-ray structure of Cat K -Complex
HN CN
ONH
CF3
H2NO2S
29
L-873724 has Similar Potency in Whole Cells and Purified CathepsinsL-873724 has Similar Potency in Whole Cells and Purified Cathepsins Trifluoroethylamine isostere gave enough potency to remove the basic P3
Selectivity profile of L-873724 is maintained in whole cell assays
Inhibition of Cathepsins, IC50 (nM)
Cathepsin B Cathepsin L Cathepsin S
Enzyme Cell Enzyme Cell Enzyme Cell
L-006235 1100 17 6300 340 47000 790
L-873724 5240 4800 264 1220 178 94
L-006235 L-873724
HN CN
ONH
O
N
SNN
HN CN
ONH
CF3
MeO2S
C. S. Li et al. BMCL 1985,16, 1985
30
L-873724 MetabolismL-873724 Metabolism
Human hepatocytes~50% metabolism
NH O
NHCF3
OH
R
N
M7: leucine hydroxylation
NH O
NHCF3
MeSO2
N
M8: hydroxyacidM12: lactone formation
NH O
CF3 O
R
NH O
OHCF3
R
NC 70141-2225 hum heps L-873,724 t=2
12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00Time10
100
%
25Oct02-014 2: Diode Array 263.801_271.9
5.22e418.92
16.12
15.7714.7214.45 15.03
17.63
17.85
19.58
L-873,724
M12
M13
M7
M8
M13: acid
NH O
CF3
OH
R
OH
? ?
L-872724 is extensively metabolized in human hepatocytes (56% metabolism)
31
Modifications to Reduce MetabolismModifications to Reduce MetabolismModify P2 to block metabolism
Add substituent to block amide cleavage and lactonization
NH
CF3
O
HN
N
MeO2S
32
L-873,724 has Similar Potency in Whole Cells and Purified CathepsinsL-873,724 has Similar Potency in Whole Cells and Purified Cathepsins Modifications result in odanacatib which maintains excellent selectivity
and activity in both enzymatic and cell-based assays
OdanacatibL-873724
Inhibition of Cathepsins, IC50 (nM)
Cathepsin SCathepsin LCathepsin BCathepsin K
0.20.2
L-873724Odanacatib
Enzyme Enzyme Enzyme EnzymeCell Cell Cell
52401034
48001050
2642995
12204843
17860
9445
Cell
35
J. Gauthier et. al. BMCL 2008, 18, 923
33
Odanacatib has Improved Pharmacokinetics in Preclinical SpeciesOdanacatib has Improved Pharmacokinetics in Odanacatib has Improved Pharmacokinetics in Preclinical SpeciesPreclinical Species Modification of L-873724 to block sites of oxidative metabolism provides
a superior pharmacokinetic profile. High recovery (>99%) after incubation with dog and human hepatocytes
OdanacatibL-873724
Pharmacokinetics
Rhesus MonkeyDogRat
L-873724Odanacatib
Cl(ml/min/kg) t1/2 (h) t1/2 (h) t1/2 (h)
6.32
2.76
1.120.13
657
7.56.1
1.718
Cl(ml/min/kg) Cl(ml/min/kg)
J. Gauthier et. al. BMCL 2008, 18, 923
34
Mean Concentration Profile of Odanacatib in Women Administered Once-Weekly Doses for 3 WeeksMean Concentration Profile of Odanacatib in Women Administered Once-Weekly Doses for 3 Weeks
Days ︵Week 1 ︶
0 1 2 3 4 5 6 7
Con
cent
ratio
n, n
M
0
100
200
300
400
500
600
25 mg OW50 mg OW100 mg OW
Days ︵Week 3 ︶
0 1 2 3 4 5 6 7 8 9 1011121314
Cat B,L,S,F IC90
Cat K IC90(bone res)
– Human half-life similar to dog; human t1/2 = 60-70 h– At therapeutic exposures, odanacatib maintains selectivity over other cathepsins
Stoch, A. et. al. Clin. Pharm. & Ther. 2009, 86, 175
35
S-CTx Mean Percent Change (95%CI) from Baseline
Effect of Odanacatib on Bone Resorption After 3 Weeks of Once-Weekly DosingEffect of Odanacatib on Bone Resorption After 3 Effect of Odanacatib on Bone Resorption After 3 Weeks of OnceWeeks of Once--Weekly DosingWeekly Dosing
0 1 3 5 7 9 11 14 16 18 21 24 28Day
-100
-75
-50
-25
0
25
50
75
S-C
TX-I
% C
hang
e fr
om B
asel
ine
Placebo5 mg 25 mg
Dose Dose Dose
50 mg 100 mg
N = 9-12/groupStoch, A. et. al. Clin. Pharm. & Ther. 2009, 86, 175
36
Selectivity of Other Cathepsin K InhibitorsSelectivity of Other Cathepsin K Inhibitors Relacatib has low selectivity towards related cathepsins (L, V, B, S) in
enzymatic assays
− Relacatib clinical development was halted after Phase I studies
Balicatib is very selective towards related cathepsins in enzymatic assays
− Development of balicatib was discontinued during Phase IIb due to morphea-like skin changes
− Cathepsin B, K, L, S and V are all expressed in human skin and have collagenase activity
− Postulate that morphea is due to lysosomotropic-based loss of selectivity
Balicatib (Novartis)
Brömme, D. Expert Opin. Investig. Drugs. 2009, 18, 585Desmarais, S. et al Molecular Pharmacology 2008, 73, 147
Relacatib (GSK)
BasicNH
HN
O
O
N
CN
NNH
HN
O
O
N
O
OS
O ON
37
Odanacatib (MK-0822)
Odanacatib has Similar Potency in Whole Cells and Purified CathepsinsOdanacatib has Similar Potency in Whole Cells and Purified Cathepsins
The low level of off-target activity of odanacatib in enzyme assays is maintained in whole cell assays
Balicatib
Cathepsin SCathepsin LCathepsin BCathepsin K
0.20.6
OdanacatibBalicatib
Enzyme Enzyme Enzyme EnzymeCell Cell Cell
10344800
105061
2995503
484348
6065000
Cell
522
Inhibition of Cathepsins, IC50 (nM)
452900
Basic
38
Effect of Cat K Inhibitors on Collagen Accumulation in Dermal FibroblastsEffect of Cat K Inhibitors on Collagen Accumulation in Dermal Fibroblasts
Odanacatib has a minimal effect on intracellular collagen accumulation compared to balicatib and the pan-cathepsin inhibitor relacatib
Inhibitor Concentration (µM)
0.01 0.1 1 10
Intra
cellu
lar C
olla
gen
Acc
umul
atio
n(F
luor
esce
nce
inte
nsity
, fol
d In
crea
sed
over
veh
icle
)
0
1
2
3
4
5
6
7
Balicatib Relacatib Odanacatib
Develop model of intracellular collagen accumulation in primary human dermal fibroblasts
J. Gauthier et. al. BMCL 2008, 18, 923
39
Odanacatib Inhibits Bone Resorption with Less Reduction of Bone FormationOdanacatib Inhibits Bone Resorption with Less Reduction of Bone Formation
Bisphosphonates and denosumab reduce the number of osteoclasts−Fewer resorption pits, reduced new bone formation
Odanacatib reduces the activity of Cat K in the osteoclast−Same number of, but shallower resorption pits−Allows new bone formation
OCOC
PP
Vehicle
OC: OsteoclastP: Resorption Pit
PPOCOC
Ob progenitor
Osteoblast (Ob)
Osteoclast
Bone formation factorsIGF-1, TGF-BMP. Wnt 10b
Odanacatib
Leung et al. Bone 2011, 49, 623
40
Historical Comparison to Alendronate
Urinary NTx
Serum BSAP
Geo
met
ric M
ean
Per
cent
Cha
nge
from
Bas
elin
e (
SE)
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
Alendronate Phase III2
3 4 5Year
21
3 4 521Year
20
20
1 Binkley et al., ASBMR 20112 Merck data on file
-80
-60
-40
-20
0
20
Odanacatib Phase IIB1
3 4 521Year
-100
-80
-60
-40
-20
0
-100
20
3 4 521Year
Odanacatib inhibits bone resorption (uNTx) while exhibiting less reduction of bone formation (BSAP) than observed with alendronate.
Differential Effects on Bone Turnover MarkersDifferential Effects on Bone Turnover Markers
41
LumbarSpine
FemoralNeck
TotalHip M
ean
Per
cent
Cha
nge
from
Bas
elin
e (±
SE
)
Alendronate Phase III2
0
5
10
15
0
5
10
0
5
10
3 4 5Year
21
3 4 5Year
21
3 4 5Year
21
Odanacatib Phase IIB1
0
5
10
15
0
5
10
0
5
10
3 4 5Year
21
3 4 5Year
21
3 4 5Year
21
Historical Comparison to Alendronate
Odanacatib: Phase IIb Study 5Odanacatib: Phase IIb Study 5--Year Data Year Data Bone Mineral Density (DXA)Bone Mineral Density (DXA) Odanacatib progressively increases BMD over 5 years at lumbar spine, femoral
neck and total hip
42
SummarySummarySummary Early inhibitors were found to accumulate in lysosomes thereby lowering
their selectivity towards related cathepsins in functional assays
Optimized leads produced selective non-basic inhibitors
Optimized non-basic leads reduced metabolism and improved pharmacokinetic properties
In post-menopausal women, odanacatib treatment:− Demonstrates less suppression of markers of bone formation than has been
observed with alendronate*− Progressively increases BMD over 5 years at lumbar spine, femoral neck,
and total hip
* Historical comparison
Recommended