DiscoveryDiscovery andand developmentdevelopment ofof odanacatib:odanacatib: AA selectiveselective cathepsincathepsin KK inhibitorinhibitor forfor thethe treatmenttreatment ofof osteoporosisosteoporosis

Shawn J. Stachel On behalf of the odanacatib discovery and product development teams Merck Research Laboratories

8th RSC-SCI Symposium on Proteinase Inhibitor Design

April 16, 2013

1 AcknowledgementsAcknowledgements Biology Chemistry Process Chemistry Bone Biology (WP) Christine Brideau Kevin Bateman Paul O’Shea Don Kimmel Wanda Cromlish Christopher Bayly Dean Bender Sevgi Rodan Sylvie Desmarais Cameron Black Mirlinda Biba Gideon Rodan Jean-Pierre Falgueyret Michael Boyd Jennifer Chilenski Le Duong Louis-Jacques Fortin Nathalie Chauret Jimmy DaSilva Pat Masarachia Sonia Lamontagne Sheldon Crane Rich Desmond Brenda Pennypacker France Landry Stephen Day Paul Devine Maureen Pickarski Frederic Masse Jacques Yves Gauthier Pete Dormer Gregg Wesolowski Dave Percival Robert Houle Bruce Foster Ya Zhuo Denis Riendeau Elise Isabel Don Guathier Pharmaceutical R&D Paul Tawa C.K. Lau Danny Gauvreau Cynthia Bazin Jennifer Wang Serge Leger Francis Gosselin Sophie-Dorothee Clas Comp. Med. Tammy LeRiche Derek Henderson Elizabeth Kwong Stephanie Alleyn Jean-Francois Levesque Greg Hughes Pauline Luk Liette Belair Chun-Sing Li John Leazer Rafik Naccache Joel Bosquet Christophe Mellon Bill Leonard Wayne Parent Carl Brière Renata Oballa John Limanto Suzanne Spagnoli Nancy Kelly Joel Robichaud Christian Nadeau Dendi Susanto Gayle Lapointe Bruno Roy Thorsten Rosner Hongshi Yu Mira Lavoie John Scheigetz Kara Rubin Safety Assessment Sonia Lesvesque Carmai Seto Ali Shafiee Laura Gumprecht Denis Normandin Michel Therien Veena Upadhyay Cindy Fishman Karen Ortega Laird Trimble Chris Welch Pharmacology Roberta Rasori Jean-Francois Truchon Clinical Development Sylvie Toulmond Josianne Rozon Vouy-Linh Truong Aubrey Stoch Tony Lombardi Wayne Sturkenboom Qingping Wang Deborah Miller Albert Leung Celera Simon Wong 2 :Osteoporosis: AA ContinuingContinuing DiseaseDisease BurdenBurden

. 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

From the International Osteoporosis Foundation . 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: 66 2 International Osteoporosis Foundation statistics. 3 BoneBone RemodelingRemodeling

Healthy: = formation Osteoporosis: Bone resorption > formation

4 OsteoclastOsteoclast –– TheThe TargetTarget CellCell forfor CathepsinCathepsin KK InhibitionInhibition

Trans- endocytosis

Electron micrograph of an osteoclast on bone N Lysosomes N

Sealing Zone

pH=5

Collagen

Bone resorption by osteoclasts is the initial step in remodeling

Rodan & Duong Bone Key 2008, 5, 6 5 CathepsinCathepsin KK DeficiencyDeficiency

. 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

Henri de Toulouse-Lautrec . Cat K null mice4 1 Inaoka, et al, BBRC 1995, 206, 89 – Osteopetrotic phenotype 2 Schilling, et al, Osteoporosis Int 2007, 18, 659 3 Saftig PNAS 1998, 95, 13453. – Increased bone density 4 Gelb, et al, Science 1996, 273, 1236 – Otherwise healthy and fertile

6 CathepsinCathepsin KK asas aa TherapeuticTherapeutic TargetTarget

. 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

7 SubstrateSubstrate toto Inhibitor:Inhibitor: WarheadWarhead

. Use knowledge of mechanism to convert substrate into inhibitor:

HS-Enz O O HO S-Enz O - H2N-R' H2O R' R' R N R N R S-Enz + Enz-SH R OH H H Tetrahedral Acyl enzyme intermediate intermediate

. 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.8 Chem. 1995, 38, 3193 SubstrateSubstrate toto Inhibitor:Inhibitor: RecognitionRecognition SequenceSequence

. Cathepsin K cleaves Type I collagen at multiple positions . Recognition sequence1: Gly-Leu-Lys—Gly-His

P3 P2 P1 P1’P2’

P2 P2

P1' O O O H O O H H H N S N N N N N N N HN H O H O H O N P3 P3 N P1 NH 2 P ' P1 2 APC3328

. 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, 241 2McGrath, M. E.; Klaus, J. L; Barnes, M. G.; Brömme, D. Nat. Struct. Biol. 1997, 4, 105 3 Brömme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer,9 J. T Biochem. J. 1996, 315, 85 OpportunitiesOpportunities forfor InhibitorInhibitor DesignDesign

• Co-crystal reveals key interactions with cathepsin K and opportunities for obtaining selectivity

– S1 pocket is a narrow groove on enzyme – S2 pocket suggests accommodation of alternative hydrophobic groups 61 – S3 sub-site contains aspartic acid (Asp ) that may be exploitable for selectivity 66 158 – P2-P1 amide forms key interaction with enzyme backbone (Gly , Asn ) 66 – P2-P3 amide: NH hydrogen-bond to Gly , oxygen points towards solvent S2

O H O O N S N N S3 HN H O

S1

McGrath, M. E.; Klaus, J. L; Barnes, M. G.; Brömme, D Nat. Struct. Biol. 1997, 4, 105 10 ReversibleReversible InhibitorsInhibitors

. Irreversible inhibitors have potential liabilities . Vinyl sulfone can be replaced by nitrile (electrophilic) – Adds cysteine reversibly to form thioimidate

O O H N S Enz-SH N N H O HN O

Nitrile-based inhibitor

. Optimization to dipeptide nitrile

L-006235

Cat K IC50 = 0.2 nM

J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520 11 SelectiveSelective InhibitionInhibition ofof CathepsinCathepsin KK isis ImportantImportant toto AvoidAvoid PotentialPotential OffOffOff-target--targettarget ActivityActivity

Cathepsins

Cysteine Cathepsins Aspartyl Cathepsins Serine Cathepsins B, C, F, H, K, L, O, S, V, W, Z D, E A, G

. 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. 12 L-006235L-006235 :: AA Potent,Potent, Selective,Selective, ReversibleReversible DipeptidicDipeptidic NitrileNitrile InhibitorInhibitor ofof CathepsinCathepsin KK

IC50 (nM) Cat K Cat B Cat L Cat S Cat F

0.2 1100 6300 47000 3000

– >5000-fold selective in purified enzyme assays – Active in rabbit and monkey models of osteoporosis

J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520 13 LLL-006235--006235006235 inin CathepsinCathepsin KK

Asp61

2.9

2.9

Asn166

Cys25 3.0

Gly66

14 LossLoss ofof SpecificitySpecificity ofof CathepsinCathepsin KK Inhibition:Inhibition: WholeWhole CellCell AssayAssay

Inhibition of Cathepsins, IC50 (nM) Cathepsin K Cathepsin B Cathepsin L Cathepsin S Enzyme Cell EnzymeCell Enzyme Cell Enzyme Cell

L-006235 0.2 5 1100 17 6300 340 47000 790

L-006235

– High selectivity profile of L-006235 is lost in whole cell assays

J. Palmer. et. al. J. Med. Chem. 2005, 48, 7520 15 Hypothesis:Hypothesis: BasicBasic InhibitorsInhibitors AccumulateAccumulate inin AcidicAcidic LysosomesLysosomes andand InhibitInhibit Off-TargetOff-Target CathepsinsCathepsins

. Lysosomotropism: accumulation of lipophilic weak bases in acidic sub-cellular compartments Lysosome Plasma Membrane

pH ~5 L-006235 Merged BH+ pH ~7

B B pH ~7 DND-99 (lyso)

L-006,235 Co-localization in live HUVECs weak basic amine

J. Falgueyret et. al. J. Med. Chem 2005, 48, 7535 16 CatCat KK InhibitorsInhibitors inin WholeWhole CellCell AssaysAssays

Inhibition of Cathepsins, IC50 (nM) Cathepsin K Cathepsin B Cathepsin L Cathepsin S Enzyme EnzymeCell Enzyme Cell Enzyme Cell

L-006235 0.2 1100 17 6300 340 47000 790 Cmpd 2 2.3 4200 2900 24000 >10000 27000 >10000

O O Basic H N Neutral H N N N N N H H N O N O N N O N S S L-006235 Cmpd 2 – 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 17 WhyWhy havehave aa BasicBasic Substituent?Substituent?

. 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

18 SARSAR OptimizationOptimization EffortsEfforts

N N O N O N O N H N CN N N H O N N S O Ar

N R S R O O H S N R R O – Extensive SAR studies on dipeptide framework resulted in loss of selectivity and/or potency – Abandoned dipeptide series of inhibitors 19 AmideAmide ReplacementReplacement 66 158 . P2-P1 amide forms key interaction with enzyme backbone (Gly , Asn ) 66 but, P2-P3 amide NH hydrogen-bond to Gly , oxygen points towards solvent

Loss of O H N N CN H O selectivity

Cat K = 73 nM Cat K = 51 nM Cat L = 3666 nM (50x) Cat L = 42 nM (0.8x) Cat S = 3401 nM (46x) Cat S = 41 nM (0.8x) Cat B = >10000 nM (137x) Cat B = 1903 nM (37x)

Increase in Cat K = 56 nM Cat L = 498 nM (9x) Cat S = 1578 nM (28x) selectivity Cat B = >10000 nM (>180) . Amide bond can be replaced but loss in Cat K potency

. Selectivity can still be achieved without P2-P3 amide

J. Robichaud et. al. BMCL 2004, 14, 4291 20 FurtherFurther OptimizationOptimization ofof AmideAmide ReplacementReplacement

. High selectivity can still be achieved without P2-P3 amide with addition of basic P3 group

HN N H Potency N CN O selectivity (R)-2 Cat K = 56 nM Cat K = 11 nM Cat L = 498 nM (9x) Cat L = 3950 nM (359x) Cat S = 1578 nM (28x) Cat S = 2010 nM (183x) Cat B = >10000 nM (>180) Cat B = 3725 nM (339x)

J. Robichaud et. al. BMCL 2004, 14, 4291 J. Robichaud et. al. J. Med. Chem. 2003, 46, 3709 21 ReRe--AdditionAddition ofof aa HydrogenHydrogen--BondBond DonorDonor

. Additional of hydrogen bond donor is favorable for cat K potency.

X = Cat K (IC50) X = Cat K (IC50) X = Cat K (IC50) NH 54 nM NH 72 nM NH 208 nM O 1147 nM O 1475 nM O 2999 nM

CH2 2353 nM CH2 3394 nM CH2 2349 nM

J. Robichaud et. al. BMCL 2004, 14, 4291 22 PotencyPotency andand SelectivitySelectivity OptimizationOptimization

selectivity

Cat K = 2 nM Cat K = 3 nM Cat L = 108 nM (54x) Cat L = 2101 nM (700x) Cat S = 24 nM (12x) Cat S = 158 nM (53x) Cat B = 26 nM (13x) Cat B = 1812 nM (604x)

. Selectivity and potency can still be achieved without P2-P3 amide with addition of basic P3 group

HN N Cat K = 11 nM H Cat L = 3950 nM (359x) N CN Cat S = 2010 nM (183x) O Cat B = 3725 nM (339x) (R)-2 J. Robichaud et. al. BMCL 2004, 14, 4291 23 AnotherAnother PeptidomimeticPeptidomimetic

O H N N CN N H O N N S

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

OO CF3 O N N N N H H H H O O

M. Zanda et. al ChemMedChem 2007, 2,1693 24 CFCF3 AmideAmide Replacement:Replacement: PP2 LeucineLeucine vsvs CyclohexylCyclohexyl

50 50

O O H H N CN N CN N N H H O O

. 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 W. C. Black et. al. BMCL 2005, 15, 4741 Black, W. C.; Percival, M. D. ChemBioChem 2006, 7, 1525 25 CFCF33 AmideAmide ReplacementReplacement

IC50 (nM) Cat K Cat B Cat L Cat S O H NCN N 0.2 1100 6300 47000 L-006235 N H O N N S CF3 H NCN N 0.03 3315 26 848 H N O 3 N N S

CF3 H N CN N H O 0.005 4 1110 47 451 N HN

. Phenyl piperazine has greater potency and selectivity than thiazole piperazine . Can this exquiste potency/selectivity advantage be extended to non-basic inhibitors?

W. C. Black et. al. BMCL 2005, 15, 4741 26 ““NonNon--basicbasic”” PP3 SubstituentsSubstituents

L-873724

. Non-basic derivatives in this series are potent and selective . L-873724 stands out as best compound in this series

C. S. Li et al. BMCL 1985,16, 1985 27 X-ray structure of CF 3 H NCN N WhyWhy areare TrifluoroethylaminesTrifluoroethylamines soso Potent?Potent? H Cat K -Complex O

H2NO2S

28 L-873724L-873724 hashas SimilarSimilar PotencyPotency inin WholeWhole CellsCells andand PurifiedPurified CathepsinsCathepsins

. Trifluoroethylamine isostere gave enough potency to remove the basic P3 . Selectivity profile of L-873724 is maintained in whole cell assays

O CF H 3 H NCN NCN N N H H N O O N N S MeO S L-006235 2 L-873724

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

C. S. Li et al. BMCL 1985,16, 1985 29 L-873724L-873724 MetabolismMetabolism

. L-872724 is extensively metabolized in human hepatocytes (56% metabolism)

CF 3 H N N N H NC 70141-2225 hum heps L-873,724 t=2 O 25Oct02-014 2: Diode Array 18.92 100 263.801_271.9 5.22e4 MeSO2 Human hepatocytes L-873,724 ~50% metabolism

OH M7 16.12 M12 CF CF3 17.63 3 H N OH N N N H % H O O R M13 R 17.85 M7: leucine hydroxylation M13: acid

19.58 ? ? M8 OH 15.03 15.77 14.45 14.72 CF CF 3 O 3 OH 10 Time N N 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 H H O O R R M12: lactone formation M8: hydroxyacid

30 ModificationsModifications toto ReduceReduce MetabolismMetabolism

Modify P2 to block metabolism

CF 3 H N N N H O Add substituent to block amide MeO S 2 cleavage and lactonization

31 L-873,724L-873,724 hashas SimilarSimilar PotencyPotency inin WholeWhole CellsCells andand PurifiedPurified CathepsinsCathepsins . Modifications result in odanacatib which maintains excellent selectivity and activity in both enzymatic and cell-based assays

L-873724 Odanacatib

Inhibition of Cathepsins, IC50 (nM) Cathepsin K Cathepsin B Cathepsin L Cathepsin S Enzyme Cell EnzymeCell Enzyme Cell Enzyme Cell

L-873724 0.2 3 5240 4800 264 1220 178 94 Odanacatib 0.2 5 1034 1050 2995 4843 60 45

J. Gauthier et. al. BMCL 2008, 18, 923 32 OdanacatibOdanacatib hashas ImprovedImproved PharmacokineticsPharmacokinetics inin PreclinicalPreclinical SpeciesSpecies . 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

L-873724 Odanacatib

Pharmacokinetics Rat Dog Rhesus Monkey

Cl(ml/min/kg) t1/2 (h) Cl(ml/min/kg) t1/2 (h) Cl(ml/min/kg) t1/2 (h) L-873724 6.3 2.7 1.12 6 7.5 1.7 Odanacatib 2 6 0.13 57 6.1 18

J. Gauthier et. al. BMCL 2008, 18, 923 33 MeanMean ConcentrationConcentration ProfileProfile ofof OdanacatibOdanacatib inin WomenWomen AdministeredAdministered Once-WeeklyOnce-Weekly DosesDoses forfor 33 WeeksWeeks 600 25 mg OW Cat B,L,S,F IC90 500 50 mg OW 100 mg OW

M 400 n

, n o i t

a 300 r t n e c

n 200 o C

100 Cat K IC90 (bone res) 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 8 9 1011121314 Days Week 1 Days Week 3 ︵ ︶ ︵ ︶

– 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 34 EffectEffect ofof OdanacatibOdanacatib onon BoneBone ResorptionResorption AfterAfter 33 WeeksWeeks ofof OnceOnceOnce-Weekly--WeeklyWeekly DosingDosing

S-CTx Mean Percent Change (95%CI) from Baseline

75 Placebo 50 mg 5 mg 100 mg 50 25 mg

25

0

-25

-50

-75 S-CTX-I % Change from Baseline S-CTX-I % Change -100 01357911141618212428 Day

Dose Dose Dose N = 9-12/group Stoch, A. et. al. Clin. Pharm. & Ther. 2009, 86, 175 35 SelectivitySelectivity ofof OtherOther CathepsinCathepsin KK InhibitorsInhibitors

. 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

O Basic H N CN O O N H H N O N N H O O N N S N O O Relacatib (GSK) Balicatib (Novartis)

Brömme, D. Expert Opin. Investig. Drugs. 2009, 18, 585 Desmarais, S. et al Molecular Pharmacology 2008, 73, 147 36 OdanacatibOdanacatib hashas SimilarSimilar PotencyPotency inin WholeWhole CellsCells andand PurifiedPurified CathepsinsCathepsins

Inhibition of Cathepsins, IC50 (nM) Cathepsin K Cathepsin B Cathepsin L Cathepsin S Enzyme Cell EnzymeCell Enzyme Cell Enzyme Cell

Odanacatib 0.2 5 1034 1050 2995 4843 60 45 Balicatib 0.6 22 4800 61 503 48 65000 2900

Basic

Odanacatib (MK-0822) Balicatib

The low level of off-target activity of odanacatib in enzyme assays is maintained in whole cell assays

37 EffectEffect ofof CatCat KK InhibitorsInhibitors onon CollagenCollagen AccumulationAccumulation inin DermalDermal FibroblastsFibroblasts . Develop model of intracellular collagen accumulation in primary human dermal fibroblasts

7

6 Balicatib Relacatib Odanacatib 5

ld Increased over vehicle) 4

3

2

Intracellular Collagen Accumulation Collagen Intracellular 1

0 (Fluorescence intensity, fo (Fluorescence intensity, 0.01 0.1 1 10 Inhibitor Concentration (µM)

. Odanacatib has a minimal effect on intracellular collagen accumulation compared to balicatib and the pan-cathepsin inhibitor relacatib

J. Gauthier et. al. BMCL 2008, 18, 923 38 OdanacatibOdanacatib InhibitsInhibits BoneBone ResorptionResorption withwith LessLess ReductionReduction ofof BoneBone FormationFormation

Bone formation factors . and IGF-1, TGF-BMP. Wnt 10b reduce the Osteoblast (Ob)

number of osteoclasts Ob progenitor

−Fewer resorption pits, Osteoclast reduced new bone formation . Odanacatib reduces the activity of Cat K in the Vehicle Odanacatib osteoclast −Same number of, but OO O shallower resorption pits CC O PP CC −Allows new bone PP formation OC: Osteoclast P: Resorption Pit

Leung et al. Bone 2011, 49, 623 39 DifferentialDifferential EffectsEffects onon BoneBone TurnoverTurnover MarkersMarkers . Odanacatib inhibits bone resorption (uNTx) while exhibiting less reduction of bone formation (BSAP) than observed with alendronate. Historical Comparison to Alendronate Odanacatib Phase IIB1 Alendronate Phase III2 20 Year 20 Year

SE) 21 345 21 34 5  0 0 -20 -20 Urinary NTx -40 -40 -60 -60 -80 -80 -100 -100 Year Year 21 345 21 345 20 20 0 0 -20 -20 Serum BSAP -40 -40 -60 -60 -80 -80 Geometric Mean Percent Change from Baseline ( Geometric Mean Percent Change from Baseline 1 Binkley et al., ASBMR 2011 -100 -100 2 Merck data on file 40 Odanacatib:Odanacatib: PhasePhase IIbIIb StudStudyy 55--YearYear DataData BoneBone MineralMineral DensityDensity (DXA)(DXA) . Odanacatib progressively increases BMD over 5 years at lumbar spine, femoral neck and total hip Historical Comparison to Alendronate Odanacatib Phase IIB1 Alendronate Phase III2 15 15

10 10

Lumbar ±SE) Spine 5 5

0 21 345 0 21 345 Year Year 10 10 e from Baseline ( Femoral Neck 5 5

0 0 21 345 21 345 Year Year 10 10 Total 5 5 Hip Mean Percent Chang

0 0 21 345 21 345 Year Year 41 SummarySummary

. 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 42