Target Information
| Target General Information | Top | |||||
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| Target ID |
T11388
(Former ID: TTDC00068)
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| Target Name |
Cathepsin K (CTSK)
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| Synonyms |
Cathepsin X; Cathepsin O2; Cathepsin O; CTSO2; CTSO
Click to Show/Hide
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| Gene Name |
CTSK
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Low bone mass disorder [ICD-11: FB83] | |||||
| Function |
Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.
Click to Show/Hide
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.22.38
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| Sequence |
MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH
NLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVD YRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGG YMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVA RVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGE NWGNKGYILMARNKNNACGIANLASFPKM Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T78C6N | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Odanacatib | Drug Info | Phase 3 | Osteoporosis | [2] | |
| 2 | SAR-114137 | Drug Info | Phase 1 | Pain | [3] | |
| 3 | VEL-0230 | Drug Info | Phase 1 | Rheumatoid arthritis | [4] | |
| Patented Agent(s) | [+] 6 Patented Agents | + | ||||
| 1 | Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1 | Drug Info | Patented | Pain | [5] | |
| 2 | PMID27998201-Compound-10 | Drug Info | Patented | Osteoporosis | [5] | |
| 3 | PMID27998201-Compound-12 | Drug Info | Patented | Cancer related pain | [5] | |
| 4 | PMID27998201-Compound-15 | Drug Info | Patented | Pain | [5] | |
| 5 | PMID27998201-Compound-5 | Drug Info | Patented | Cirrhosis | [5] | |
| 6 | PMID27998201-Compound-9 | Drug Info | Patented | Rheumatoid arthritis | [5] | |
| Discontinued Drug(s) | [+] 4 Discontinued Drugs | + | ||||
| 1 | Balicatib | Drug Info | Discontinued in Phase 2 | Osteoporosis | [6], [7] | |
| 2 | ONO-5334 | Drug Info | Discontinued in Phase 2 | Osteoporosis | [8] | |
| 3 | Relacatib | Drug Info | Discontinued in Phase 2 | Bone metastases | [7], [9] | |
| 4 | MIV-701 | Drug Info | Discontinued in Phase 1 | Osteoporosis | [10] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | GW-2592X | Drug Info | Preclinical | Osteoporosis | [11] | |
| 2 | L-006235-1 | Drug Info | Preclinical | Osteoarthritis | [12] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 64 Inhibitor drugs | + | ||||
| 1 | Odanacatib | Drug Info | [1], [13] | |||
| 2 | SAR-114137 | Drug Info | [3] | |||
| 3 | VEL-0230 | Drug Info | [14] | |||
| 4 | Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1 | Drug Info | [5] | |||
| 5 | PMID25399719-Compound-17 | Drug Info | [15] | |||
| 6 | PMID27998201-Compound-10 | Drug Info | [5] | |||
| 7 | PMID27998201-Compound-12 | Drug Info | [5] | |||
| 8 | PMID27998201-Compound-15 | Drug Info | [5] | |||
| 9 | PMID27998201-Compound-5 | Drug Info | [5] | |||
| 10 | PMID27998201-Compound-8 | Drug Info | [5] | |||
| 11 | PMID27998201-Compound-9 | Drug Info | [5] | |||
| 12 | Balicatib | Drug Info | [7] | |||
| 13 | ONO-5334 | Drug Info | [16], [17] | |||
| 14 | Relacatib | Drug Info | [18], [19], [20] | |||
| 15 | MIV-701 | Drug Info | [21] | |||
| 16 | GW-2592X | Drug Info | [22] | |||
| 17 | L-006235-1 | Drug Info | [23] | |||
| 18 | (S)-1-benzylcyclopentyl 1-oxohexan-2-ylcarbamate | Drug Info | [24] | |||
| 19 | (S)-tert-butyl 1-oxohexan-2-ylcarbamate | Drug Info | [24] | |||
| 20 | (S)-tert-butyl 4-methyl-1-oxopentan-2-ylcarbamate | Drug Info | [24] | |||
| 21 | 2-cyclohexylamino-pyridine-2-carbonitrile | Drug Info | [25] | |||
| 22 | 2-cyclohexylamino-pyrimidine-4-carbonitrile | Drug Info | [25] | |||
| 23 | 3-Amino-5-Phenylpentane | Drug Info | [26] | |||
| 24 | 4-cycloheptyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [27] | |||
| 25 | 4-cyclohexyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [27] | |||
| 26 | 4-cyclohexylamino-pyrimidine-2-carbonitrile | Drug Info | [25] | |||
| 27 | 4-cyclooctyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [27] | |||
| 28 | 4-phenyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [28] | |||
| 29 | 4-propyl-6-m-tolylpyrimidine-2-carbonitrile | Drug Info | [28] | |||
| 30 | AM-3701 | Drug Info | [22] | |||
| 31 | BF/PC-21 | Drug Info | [22] | |||
| 32 | Boc-Agly-Val-Agly-OEt | Drug Info | [29] | |||
| 33 | GNF-PF-5434 | Drug Info | [30] | |||
| 34 | L-873724 | Drug Info | [18] | |||
| 35 | N-(1-((cyanomethyl)carbamoyl)cyclohexyl)benzamide | Drug Info | [31] | |||
| 36 | N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile | Drug Info | [32] | |||
| 37 | N-(benzyloxycarbonyl)-leucyl-glycine-nitrile | Drug Info | [32] | |||
| 38 | N-(cyanomethyl)cyclohex-1-ene-1-carboxamide | Drug Info | [31] | |||
| 39 | N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile | Drug Info | [32] | |||
| 40 | N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile | Drug Info | [32] | |||
| 41 | N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile | Drug Info | [32] | |||
| 42 | N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile | Drug Info | [32] | |||
| 43 | N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile | Drug Info | [32] | |||
| 44 | N-(tert-butoxycarbonyl)-valyl-glycine-nitrile | Drug Info | [32] | |||
| 45 | N-acetyl-phenylalanyl-glycine-nitrile | Drug Info | [32] | |||
| 46 | N-benzoyl-phenylalanyl-glycine-nitrile | Drug Info | [32] | |||
| 47 | P2,P3 Ketoamide derivative | Drug Info | [33] | |||
| 48 | PMID16290936C1b | Drug Info | [24] | |||
| 49 | Pyrrolidine-1-carbonitrile | Drug Info | [34] | |||
| 50 | Tert-butyl (2S)-1-cyanopyrrolidine-2-carboxylate | Drug Info | [34] | |||
| 51 | TERT-BUTYL 2-CYANO-2-METHYLHYDRAZINECARBOXYLATE | Drug Info | [35] | |||
| 52 | Tert-Butyl(1s)-1-Cyclohexyl-2-Oxoethylcarbamate | Drug Info | [35] | |||
| 53 | Z-Ala-Leu-His-Agly-Ile-Val-OMe | Drug Info | [29] | |||
| 54 | Z-Ala-Leu-lle-Agly-Ile-Val-NHBzl | Drug Info | [29] | |||
| 55 | Z-Ala-Leu-lle-Agly-Ile-Val-OMe | Drug Info | [29] | |||
| 56 | Z-Ala-Leu-Nal-Agly-Ile-Val-OMe | Drug Info | [29] | |||
| 57 | Z-Ala-Leu-Phe-Agly-Ile-Val-OMe | Drug Info | [29] | |||
| 58 | Z-Ala-Leu-Tyr(Me)-Agly-Ile-Val-OMe | Drug Info | [29] | |||
| 59 | Z-Arg-Leu-Val-Agly-Ala-Gly-NH2 | Drug Info | [29] | |||
| 60 | Z-Arg-Leu-Val-Agly-Ile-Val-Trp-NH2 | Drug Info | [29] | |||
| 61 | Z-Arg-Leu-Val-Agly-Ileu-Val-OMe | Drug Info | [29] | |||
| 62 | Z-Arg-Leu-Val-Agly-Trp-Val-Ala-NH2 | Drug Info | [29] | |||
| 63 | Z-Arg-Leu-Val-Agly-Val-Ala-NH2 | Drug Info | [29] | |||
| 64 | Z-leu-Val-Agly-Val-OBzl | Drug Info | [29] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | MIV-710 | Drug Info | [22] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: N-(2-Acetamido)Iminodiacetic Acid | Ligand Info | |||||
| Structure Description | Cathepsin-K in complex with amino-oxaazabicyclo[3.3.0]octanyl containing inhibitor | PDB:6QM0 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [36] |
| PDB Sequence |
RAPDSVDYRK
9 KGYVTPVKNQ19 GQCGSCWAFS29 SVGALEGQLK39 KKTGKLLNLS49 PQNLVDCVSE 59 NDGCGGGYMT69 NAFQYVQKNR79 GIDSEDAYPY89 VGQEESCMYN99 PTGKAAKCRG 109 YREIPEGNEK119 ALKRAVARVG129 PVSVAIDASL139 TSFQFYSKGV149 YYDESCNSDN 159 LNHAVLAVGY169 GIQKGNKHWI179 IKNSWGENWG189 NKGYILMARN199 KNNACGIANL 209 ASFPKM
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| Ligand Name: Tert-Butyl(1s)-1-Cyclohexyl-2-Oxoethylcarbamate | Ligand Info | |||||
| Structure Description | Cathepsin K complexed with t-butyl(1S)-1-cyclohexyl-2-oxoethylcarbamate | PDB:1Q6K | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [37] |
| PDB Sequence |
APDSVDYRKK
10 GYVTPVKNQG20 QCGSCWAFSS30 VGALEGQLKK40 KTGKLLNLSP50 QNLVDCVSEN 60 DGCGGGYMTN70 AFQYVQKNRG80 IDSEDAYPYV90 GQEESCMYNP100 TGKAAKCRGY 110 REIPEGNEKA120 LKRAVARVGP130 VSVAIDASLT140 SFQFYSKGVY150 YDESCNSDNL 160 NHAVLAVGYG170 IQKGNKHWII180 KNSWGENWGN190 KGYILMARNK200 NNACGIANLA 210 SFPKM
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Putative inactive cathepsin L-like protein CTSL3P (CTSL3P) | 38.938 (44/113) | 3.00E-10 | |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Apoptosis | hsa04210 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Osteoclast differentiation | hsa04380 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Toll-like receptor signaling pathway | hsa04620 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Lysosome | |||||
| 2 | Osteoclast differentiation | |||||
| 3 | Toll-like receptor signaling pathway | |||||
| 4 | Rheumatoid arthritis | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| 2 | RANKL Signaling Pathway | |||||
| 3 | IL2 Signaling Pathway | |||||
| Reactome | [+] 5 Reactome Pathways | + | ||||
| 1 | Collagen degradation | |||||
| 2 | Degradation of the extracellular matrix | |||||
| 3 | Activation of Matrix Metalloproteinases | |||||
| 4 | Trafficking and processing of endosomal TLR | |||||
| 5 | MHC class II antigen presentation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | RANKL/RANK Signaling Pathway | |||||
| 2 | Osteoclast Signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8. | |||||
| REF 2 | ClinicalTrials.gov (NCT01803607) Efficacy and Safety of Odanacatib in Postmenopausal Women Previously Treated With Oral Bisphosphonate (MK-0822-076). U.S. National Institutes of Health. | |||||
| REF 3 | From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor. Eur J Pharm Biopharm. 2013 Apr;83(3):436-48. | |||||
| REF 4 | Velcura Therapeutics, Inc. to Begin Clinical Trials in Rheumatoid Arthritis Patients. Velcura Therapeutics, Inc. JANUARY 07, 2009. | |||||
| REF 5 | Cathepsin B and L inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2017 Jun;27(6):643-656. | |||||
| REF 6 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7861). | |||||
| REF 7 | Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27. | |||||
| REF 8 | ClinicalTrials.gov (NCT00532337) Controlled Study of ONO-5334 in Postmenopausal Women With Osteopenia or Osteoporosis. U.S. National Institutes of Health. | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7862). | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016480) | |||||
| REF 11 | Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019 Dec;18(12):923-948. | |||||
| REF 12 | Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012 Jun;50(6):1250-9. | |||||
| REF 13 | Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008 Jan;83(1):172-6. | |||||
| REF 14 | Discovery and parallel synthesis of a new class of cathepsin K inhibitors. Bioorg Med Chem Lett. 2001 Nov 19;11(22):2951-4. | |||||
| REF 15 | An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31. | |||||
| REF 16 | New approach for osteoporosis treatment: cathepsin K inhibitor, ONO-5334. Clin Calcium. 2011 Jan;21(1):64-9. | |||||
| REF 17 | Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females. J Clin Pharmacol. 2014 Jan;54(1):23-34. | |||||
| REF 18 | The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. | |||||
| REF 19 | A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone tur... Bone. 2007 Jan;40(1):122-31. | |||||
| REF 20 | Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J Med Chem. 2006 Mar 9;49(5):1597-612. | |||||
| REF 21 | Medivir designates MIV-710 a Candidate Drug (CD) for Osteoporosis and Osteoarthritis, 2009 | |||||
| REF 22 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2350). | |||||
| REF 23 | Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional se... J Med Chem. 2005 Dec 1;48(24):7535-43. | |||||
| REF 24 | Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83. | |||||
| REF 25 | 2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K. J Med Chem. 2007 Feb 22;50(4):591-4. | |||||
| REF 26 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 27 | Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7. | |||||
| REF 28 | 2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50. | |||||
| REF 29 | Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases. J Med Chem. 2002 Sep 12;45(19):4202-11. | |||||
| REF 30 | Substrate optimization for monitoring cathepsin C activity in live cells. Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. | |||||
| REF 31 | Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. J Med Chem. 2006 Feb 9;49(3):1066-79. | |||||
| REF 32 | Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. J Med Chem. 2005 Dec 1;48(24):7688-707. | |||||
| REF 33 | Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902. | |||||
| REF 34 | Acyclic cyanamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3039-43. | |||||
| REF 35 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 36 | Successful development of 3-oxohexahydrofuropyrrole amino acid amides as inhibitors of Cathepsin-K. | |||||
| REF 37 | Exploration of the P1 SAR of aldehyde cathepsin K inhibitors. Bioorg Med Chem Lett. 2004 Jan 5;14(1):275-8. | |||||
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