Advances in the discovery of cathepsin K inhibitors on bone resorption

References

• Bossard MJ, Tomaszek TA, Thompson SK, et al. Proteolytic activity of human osteoclast cathepsin K expression, purification, activation, and substrate identification. J Biol Chem 1996;271:12517–24.
   PubMed Web of Science ®Google Scholar
• Garnero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 1998;273:32347–52.
   PubMed Web of Science ®Google Scholar
• Consensus A. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646–50.
   PubMed Web of Science ®Google Scholar
• Brömme D, Okamoto K, Wang BB, Biroc S. Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme. J Biol Chem 1996;271:2126–32.
   PubMed Web of Science ®Google Scholar
• Zaidi M, Troen B, Moonga BS, Abe E. Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res 2001;16:1747–9.
   PubMed Web of Science ®Google Scholar
• Patil AD, Freyer AJ, Killmer L, et al. A new dimeric dihydrochalcone and a new prenylated flavone from the bud covers of Artocarpus altilis: potent inhibitors of Cathepsin K. J Nat Prod 2002;65:624–7.
   PubMed Web of Science ®Google Scholar
• McGrath ME, Klaus JL, Barnes MG, Brömme D. Crystal structure of human cathepsin K complexed with a potent inhibitor. Nat Struct Mol Biol 1997;4:105–9.
   Web of Science ®Google Scholar
• Stoch S, Wagner J. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 2008;83:172–6.
   PubMed Web of Science ®Google Scholar
• Mazid Helali A, Matin Iti F, Naina Mohamed I. Cathepsin K inhibitors: a novel target but promising approach in the treatment of osteoporosis. Curr Drug Targets 2013;14:1591–600.
   PubMed Web of Science ®Google Scholar
• Duong LT, Leung AT, Langdahl B. Cathepsin K inhibition: a new mechanism for the treatment of osteoporosis. Calcif Tissue Int 2016;98:381–97.
   PubMed Web of Science ®Google Scholar
• Hussein H, Dulin J, Smanik L, et al. Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover. J Vet Pharmacol Ther 2017;40:327–34.
   PubMed Web of Science ®Google Scholar
• Tanaka M, Hashimoto Y, Hasegawa C, et al. Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis. BMC Musculoskelet Disord 2017;18:267.
   PubMed Web of Science ®Google Scholar
• Tu L, Rui K, Feng H, Wang Z. Safety of the cathepsin K inhibitor odanacatib in postmenopausal women with osteopenia or osteoporosis: a meta-analysis. Int J Clin Exp Med 2017;10:5977–84.
   Web of Science ®Google Scholar
• Allen JG, Fotsch C, Babij P. Emerging targets in osteoporosis disease modification. J Med Chem 2010;53:4332–53.
   PubMed Web of Science ®Google Scholar
• Wijkmans J, Gossen J. Inhibitors of cathepsin K: a patent review (2004–2010). Expert Opin Ther Pat 2011;21:1611–29.
   PubMed Web of Science ®Google Scholar
• Yamashita DS, Dodds RA. Cathepsin K and the design of inhibitors of cathepsin K. Curr Pharm Des 2000;6:1–24.
   PubMed Web of Science ®Google Scholar
• Yasuda Y, Kaleta J, Brömme D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 2005;57:973–93.
   PubMed Web of Science ®Google Scholar
• Kim TS, Tasker AS. Non-covalent cathepsin K inhibitors for the treatment of osteoporosis. Curr Top Med Chem 2006;6:355–60.
   PubMed Web of Science ®Google Scholar
• Yamashita DS, Smith WW, Zhao B, et al. Structure and design of potent and selective cathepsin K inhibitors. JACS 1997;119:11351–2.
   Web of Science ®Google Scholar
• Shi G-P, Munger J, Meara J, et al. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J Biol Chem 1992;267:7258–62.
   PubMed Web of Science ®Google Scholar
• DesJarlais RL, Yamashita DS, Oh HJ, et al. Use of X-ray co-crystal structures and molecular modeling to design potent and selective non-peptide inhibitors of cathepsin K. JACS 1998;120:9114–15.
   Web of Science ®Google Scholar
• Marquis RW, Ru Y, LoCastro SM, et al. Azepanone-based inhibitors of human and rat cathepsin K. J Med Chem 2001;44:1380–95.
   PubMed Web of Science ®Google Scholar
• Yamashita DS, Marquis RW, Xie R, et al. Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J Med Chem 2006;49:1597–612.
   PubMed Web of Science ®Google Scholar
• Kumar S, Dare L, Vasko-Moser J, et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 2007;40:122–31.
   PubMed Web of Science ®Google Scholar
• Marquis RW, Ru Y, Zeng J, et al. Cyclic ketone inhibitors of the cysteine protease cathepsin K. J Med Chem 2001;44:725–36.
   PubMed Web of Science ®Google Scholar
• Boyd MJ, Crane SN, Robichaud J, et al. Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors. Bioorg Med Chem Lett 2009;19:675–9.
   PubMed Web of Science ®Google Scholar
• Prasit P, Bayly CI, Robichaud JS, et al. Cathepsin cysteine protease inhibitors: Google Patents; 2006.
   Google Scholar
• Robichaud J, Oballa R, Prasit P, et al. A novel class of nonpeptidic biaryl inhibitors of human cathepsin K. J Med Chem 2003;46:3709–27.
   PubMed Web of Science ®Google Scholar
• Grabowskal U, Chambers T, Shiroo M. Recent developments in cathepsin K inhibitor design. Curr Opin Drug Discovery Dev 2005;8:619–30.
   PubMed Web of Science ®Google Scholar
• Fuller K, Lawrence KM, Ross JL, et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 2008;42:200–11.
   PubMed Web of Science ®Google Scholar
• Ochi Y, Yamada H, Mori H, et al. Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone 2011;49:1351–6.
   PubMed Web of Science ®Google Scholar
• Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Mine Res 2014;29:458–66.
   PubMed Web of Science ®Google Scholar
• Quibell M, Benn A, Flinn N, et al. Bicyclic peptidomimetic tetrahydrofuro [3, 2-b] pyrrol-3-one and hexahydrofuro [3, 2-b] pyridine-3-one based scaffolds: synthesis and cysteinyl proteinase inhibition. Bioorg Med Chem 2004;12:5689–710.
   PubMed Web of Science ®Google Scholar
• Quibell M, Watts JP, Furo [3, 2-b] pyrrol derivatives: Google Patents; 2010.
   Google Scholar
• Quibell M, Watts JP, Furo [3, 2-B] pyrrol-3-one derivatives and their use as cysteinyl proteinase inhibitors: Google Patents; 2014.
   Google Scholar
• Quibell M, Watts JP, Tetrahydrofuro (3, 2-B) pyrrol-3-one derivatives as inhibitors of cysteine proteinases: Google Patents; 2010.
   Google Scholar
• Quibell M, Watts JP, Tetrahydrofuro [3, 2-B] pyrrol-3-ones as cathepsin K inhibitors: Google Patents; 2010.
   Google Scholar
• Boros EE, Deaton DN, Hassell AM, et al. Exploration of the P 2–P 3 SAR of aldehyde cathepsin K inhibitors. Bioorg Med Chem Lett 2004;14:3425–9.
   PubMed Web of Science ®Google Scholar
• Buysse A, Mendonca R, Palmer J, et al. Novel compounds and compositions as protease inhibitors: Google Patents; 2002.
   Google Scholar
• Altmann E, Betschart C, Gohda K, et al. Dipeptide nitriles: Google Patents; 2002.
   Google Scholar
• Greenspan PD, Clark KL, Tommasi RA, et al. Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design. J Med Chem 2001;44:4524–34.
   PubMed Web of Science ®Google Scholar
• Ward YD, Thomson DS, Frye LL, et al. Design and synthesis of dipeptide nitriles as reversible and potent cathepsin S inhibitors. J Med Chem 2002;45:5471–82.
   PubMed Web of Science ®Google Scholar
• Lewis Jr CA, Wolfenden R. Thiohemiacetal formation by inhibitory aldehydes at the active site of papain. Biochemistry 1977;16:4890–5.
   PubMed Web of Science ®Google Scholar
• Moon JB, Coleman RS, Hanzlik RP. Reversible covalent inhibition of papain by a peptide nitrile. Carbon-13 NMR evidence for a thioimidate ester adduct. JACS 1986;108:1350–1.
   Web of Science ®Google Scholar
• Suzue S, Irikura T. Studies on hepatic agents. I. Synthesis of aminoacyl (and hydroxyacyl) aminoacetonitriles. Chem Pharm Bull 1968;16:1417–32.
   PubMed Web of Science ®Google Scholar
• Robichaud J, Bayly C, Oballa R, et al. Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors. Bioorg Med Chem Lett 2004;14:4291–5.
   PubMed Web of Science ®Google Scholar
• Altmann E, Aichholz R, Betschart C, et al. Dipeptide nitrile inhibitors of cathepsin K. Bioorg Med Chem Lett 2006;16:2549–54.
   PubMed Web of Science ®Google Scholar
• Palmer JT, Bryant C, Wang D-X, et al. Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K. J Med Chem 2005;48:7520–34.
   PubMed Web of Science ®Google Scholar
• Soung DY, Gentile MA, Duong LT, Drissi H. Effects of pharmacological inhibition of cathepsin K on fracture repair in mice. Bone 2013;55:248–55.
   PubMed Web of Science ®Google Scholar
• Zimmermann J, Goessl C, Combinations of a cathepsin k inhibitor and a bisphosphonate in the treatment of bone metastasis, tumor growth and tumor-induced bone loss: Google Patents; 2004.
   Google Scholar
• Novartis A, Use of cathepsin K inhibitors in severe bone loss diseases. WO05049028; 2005.
   Google Scholar
• Falgueyret JP, Desmarais S, Oballa R, et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J Med Chem 2005;48:7535–43.
   PubMed Web of Science ®Google Scholar
• Adami S, Supronik J, Hala T, et al. Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J Bone Miner Res 2006;21:S24.
   Web of Science ®Google Scholar
• Papanastasiou P, Ortmann C, Olson M, et al. Effect of three month treatment with the cathepsin-k inhibitor, balicatib, on biochemical markers of bone turnover in postmenopausal women: evidence for uncoupling of bone resorption and bone formation. J Bone Miner Res 2006;21:S59.
   Web of Science ®Google Scholar
• Bühling F, Röcken C, Brasch F, et al. Pivotal role of cathepsin K in lung fibrosis. Am J Pathol 2004;164:2203–16.
   PubMed Web of Science ®Google Scholar
• Borišek J, Vizovišek M, Sosnowski P, et al. Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as potent cathepsin K inhibitors. J Med Chem 2015;58:6928–37.
   PubMed Web of Science ®Google Scholar
• Yuan X-Y, Fu D-Y, Ren X-F, et al. Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling. Org Biomolec Chem 2013;11:5847–52.
   PubMed Web of Science ®Google Scholar
• Gante J. Peptidomimetics-tailored enzyme inhibitors. Angew Chem Int Ed 1994;33:1699–720.
   Web of Science ®Google Scholar
• Volonterio A, Bellosta S, Bravin F, et al. Synthesis, structure and conformation of partially-modified retro-and retro-inverso [NHCH (CF3)] Gly peptides. Chem Eur J 2003;9:4510–22.
   PubMed Web of Science ®Google Scholar
• Black WC, Bayly CI, Davis DE, et al. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg Med Chem Lett 2005;15:4741–4.
   PubMed Web of Science ®Google Scholar
• Li CS, Deschenes D, Desmarais S, et al. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg Med Chem Lett 2006;16:1985–9.
   PubMed Web of Science ®Google Scholar
• Guay J, Riendeau D, Mancini J. Cloning and expression of rhesus monkey cathepsin K. Bone 1999;25:205–9.
   PubMed Web of Science ®Google Scholar
• Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett.
   Web of Science ®Google Scholar
• Law S, Andrault P-M, Aguda AH, et al. Identification of mouse cathepsin K structural elements that regulate the potency of odanacatib. Biochem J 2017;474:851–64.
   PubMed Web of Science ®Google Scholar
• Falgueyret J-P, Black WC, Cromlish W, et al. An activity-based probe for the determination of cysteine cathepsin protease activities in whole cells. Analyt Biochem 2004;335:218–27.
   PubMed Web of Science ®Google Scholar
• Pennypacker BL, Duong LT, Cusick TE, et al. Cathepsin K inhibitors prevent bone loss in estrogen‐deficient rabbits. J Bone Miner Res 2011;26:252–62.
   PubMed Web of Science ®Google Scholar
• Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 2011;26:242–51.
   PubMed Web of Science ®Google Scholar
• Stoch S, Zajic S, Stone J, et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double‐blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther 2009;86:175–82.
   PubMed Web of Science ®Google Scholar
• Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 2012;27:2251–8.
   PubMed Web of Science ®Google Scholar
• Mcclung MR, Langdahl B, Papapoulos S, et al. Odanacatib anti-fracture efficacy and safety in postmenopausal women with osteoporosis: results from the phase III long-term odanacatib fracture trial. Arthritis Rheum 2014;66:S987.
   Web of Science ®Google Scholar
• Harsløf T, Langdahl BL. New horizons in osteoporosis therapies. Curr Opin Pharmacol 2016;28:38–42.
   PubMed Web of Science ®Google Scholar
• Cabal A, Williams DS, Jayakar RY, et al. Long-term treatment with odanacatib maintains normal trabecular biomechanical properties in ovariectomized adult monkeys as demonstrated by micro-CT-based finite element analysis. Bone Rep 2017;6:26–33.
   PubMedGoogle Scholar
• Hirsch HD, Sikon A, Thacker HL. Osteoporosis for the female patient. In: Falcone T, Hurd W, eds. Clinical reproductive medicine and surgery. Cham (Switzerland): Springer; 2017:195–208.
   Google Scholar
• Isabel E, Bateman KP, Chauret N, et al. The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor. Bioorg Med Chem Lett 2010;20:887–92.
   PubMed Web of Science ®Google Scholar
• Crane SN, Black WC, Palmer JT, et al. β-Substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. J Med Chem 2006;49:1066–79.
   PubMed Web of Science ®Google Scholar
• Falgueyret J-P, Oballa RM, Okamoto O, et al. Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J Med Chem 2001;44:94–104.
   PubMed Web of Science ®Google Scholar
• Robichaud J, Bayly CI, Black WC, et al. β-Substituted cyclohexanecarboxamide cathepsin K inhibitors: modification of the 1,2-disubstituted aromatic core. Bioorg Med Chem Lett 2007;17:3146–51.
   PubMed Web of Science ®Google Scholar
• Robichaud J, Black WC, Thérien M, et al. Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis. J Med Chem 2008;51:6410–20.
   PubMed Web of Science ®Google Scholar
• Dossetter AG, Beeley H, Bowyer J, et al. (1 R, 2 R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1, 3, 4, 5-tetrahydropyrido [4, 3-b] indole-2-carbonyl) cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the treatment of osteoarthritis. J Med Chem 2012;55:6363–74.
   PubMed Web of Science ®Google Scholar
• Altmann E, Aichholz R, Betschart C, et al. 2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K. J Med Chem 2007;50:591–4.
   PubMed Web of Science ®Google Scholar
• Teno N, Miyake T, Ehara T, et al. Novel scaffold for cathepsin K inhibitors. Bioorg Med Chem Lett 2007;17:6096–100.
   PubMed Web of Science ®Google Scholar
• Organon N. 2-Cyano-1,3,5-triazine-4,6-diamine derivatives. WO05011703; 2005.
   Google Scholar
• Rankovic Z, Cai J, Kerr J, et al. Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. Bioorg Med Chem Lett 2010;20:1524–7.
   PubMed Web of Science ®Google Scholar
• Cai J, Baugh M, Black D, et al. 6-Phenyl-1H-imidazo [4, 5-c] pyridine-4-carbonitrile as cathepsin S inhibitors. Bioorg Med Chem Lett 2010;20:4350–4.
   PubMed Web of Science ®Google Scholar
• Teno N, Masuya K, Ehara T, et al. Effect of cathepsin K inhibitors on bone resorption. J Med Chem 2008;51:5459–62.
   PubMed Web of Science ®Google Scholar
• Organon N, 6-Phenyl-1H-imidazo [4, 5-c] pyridine-4-carbonitrile derivatives as cathepsin inhibitors. WO07080191; 2007.
   Google Scholar
• Shinozuka T, Shimada K, Matsui S, et al. 4-Aminophenoxyacetic acids as a novel class of reversible cathepsin K inhibitors. Bioorg Med Chem Lett 2006;16:1502–5.
   PubMed Web of Science ®Google Scholar
• Setti EL, Davis D, Janc JW, et al. 4-Disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity. Bioorg Med Chem Lett 2005;15:1529–34.
   PubMed Web of Science ®Google Scholar
• Setti EL, Davis D, Chung T, McCarter J. 3, 4-Disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P2 elements for selectivity. Bioorg Med Chem Lett 2003;13:2051–3.
   PubMed Web of Science ®Google Scholar
• Altmann E, Renaud J, Green J, et al. Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors. J Med Chem 2002;45:2352–4.
   PubMed Web of Science ®Google Scholar
• Altmann E, Green J, Tintelnot-Blomley M. Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin K-investigating P 1′ substituents. Bioorg Med Chem Lett 2003;13:1997–2001.
   PubMed Web of Science ®Google Scholar
• Shinozuka T, Shimada K, Matsui S, et al. Arylamine based cathepsin K inhibitors: investigating P3 heterocyclic substituents. Bioorg Med Chem 2006;14:6807–19.
   PubMed Web of Science ®Google Scholar
• Shinozuka T, Shimada K, Matsui S, et al. Potent and selective cathepsin K inhibitors. Bioorg Med Chem 2006;14:6789–806.
   PubMed Web of Science ®Google Scholar
• Unoki G, Hayamizu T, Eguchi H, et al. Cysteine protease inhibitors: Google Patents; 2009.
   Google Scholar
• Novinec M, Korenč M, Caflisch A, et al. A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods. Nature Commun 2014;5:3287.
   PubMed Web of Science ®Google Scholar
• Asagiri M, Hirai T, Kunigami T, et al. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 2008;319:624–7.
   PubMed Web of Science ®Google Scholar
• Wang ZQ, Li JL, Sun YL, et al. Chinese herbal medicine for osteoporosis: a systematic review of randomized controlled trails. Evid-Based Complementary Altern Med 2013;2013:356260.
   PubMed Web of Science ®Google Scholar
• Mukwaya E, Xu F, Wong MS, Zhang Y. Chinese herbal medicine for bone health. Pharmaceut Biol 2014;52:1223–8.
   PubMed Web of Science ®Google Scholar
• Jeong JC, Lee BT, Yoon CH, et al. Effects of Drynariae rhizoma on the proliferation of human bone cells and the immunomodulatory activity. Pharmacol Res 2005;51:125–36.
   PubMed Web of Science ®Google Scholar
• Chen LL, Lei LH, Ding PH, et al. Osteogenic effect of Drynariae rhizoma extracts and Naringin on MC3T3-E1 cells and an induced rat alveolar bone resorption model. Arch Oral Biol 2011;56:1655–62.
   PubMed Web of Science ®Google Scholar
• Sun JS, Lin CY, Dong GC, et al. The effect of Gu-Sui-Bu (Drynaria fortunei J. Sm) on bone cell activities. Biomaterials 2002;23:3377–85.
   PubMed Web of Science ®Google Scholar
• Guo Y, Li Y, Xue L, et al. Salvia miltiorrhiza: an ancient Chinese herbal medicine as a source for anti-osteoporotic drugs. J Ethnopharmacol 2014;155:1401–16.
   PubMed Web of Science ®Google Scholar
• Patil AD, Freyer AJ, Carte B, et al. Haploscleridamine, a novel tryptamine-derived alkaloid from a sponge of the order Haplosclerida: an inhibitor of cathepsin K. J Natural Prod 2002;65:628–9.
   PubMed Web of Science ®Google Scholar
• Qiu Z-C, Dong X-L, Dai Y, et al. Discovery of a new class of cathepsin K inhibitors in Rhizoma drynariae as potential candidates for the treatment of osteoporosis. Int J Mol Sci 2016;17:2116.
   Web of Science ®Google Scholar
• Panwar P, Soe K, Guido RV, et al. A novel approach to inhibit bone resorption: exosite inhibitors against cathepsin K. Brit J Pharmacol 2016;173:396–410.
   PubMed Web of Science ®Google Scholar
• Sharma V, Panwar P, O’Donoghue AJ, et al. Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor. Biochem J 2015;465:163–73.
   PubMed Web of Science ®Google Scholar
• Chen K, Ge B, Liu X, et al. Icariin inhibits the osteoclast formation induced by RANKL and macrophage-colony stimulating factor in mouse bone marrow culture. Die Pharm 2007;62:388–91.
   PubMed Web of Science ®Google Scholar
• Hsieh T-P, Sheu S-Y, Sun J-S, Chen M-H. Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-κB regulated HIF-1α and PGE2 synthesis. Phytomedicine 2011;18:176–85.
   PubMed Web of Science ®Google Scholar
• Sun P, Liu Y, Deng X, et al. An inhibitor of cathepsin K, icariin suppresses cartilage and bone degradation in mice of collagen-induced arthritis. Phytomedicine 2013;20:975–9.
   PubMed Web of Science ®Google Scholar
• Dean JH. Immunotoxicology and immunopharmacology. New York (NY): Raven Press; 1985.
   Google Scholar
• Lecaille F, Kaleta J, Brömme D. Human and parasitic papain-like cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design. Chem Rev 2002;102:4459–88.
   PubMed Web of Science ®Google Scholar
• McGrath ME, Klaus JL, Barnes MG, Brömme D. Crystal structure of human cathepsin K complexed with a potent inhibitor. Nat Struct Mol Biol 1997;4:105.
   Web of Science ®Google Scholar
• Wang D, Li W, Pechar M, et al. Cathepsin K inhibitor-polymer conjugates: potential drugs for the treatment of osteoporosis and rheumatoid arthritis. Int. J. Pharm 2004;277:73–9.
   PubMed Web of Science ®Google Scholar
• Wang D, Pechar M, Li W, et al. Inhibition of cathepsin K with lysosomotropic macromolecular inhibitors. Biochemistry 2002;41:8849–59.
   PubMed Web of Science ®Google Scholar
• Lu J, Jiang F, Lu A, Zhang G. Linkers having a crucial role in antibody-drug conjugates. Int J Molec Sci 2016;17:561.
   PubMed Web of Science ®Google Scholar
• Yu NY, Fathi A, Murphy CM, et al. Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly (d, l-lactide-co-glycolide) nanospheres. J Biomed Mater Res Part B Appl Biomater 2017;105:136–44.
   PubMed Web of Science ®Google Scholar