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A Selective Cathepsin K Inhibitor for the Treatment of Osteoporosis

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A Selective Cathepsin K Inhibitor for the Treatment of Osteoporosis 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: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: Bone resorption = 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 Cathepsin K 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
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