odanacatib and Disease-Models--Animal

Cathepsin K is a key enzyme involved in the degradation of organic bone matrix by osteoclasts. Inhibition of bone resorption observed in human and animal models deficient for cathepsin K has identified this enzyme as a suitable target for intervention by small molecules with the potential to be used as therapeutic agents in the treatment of osteoporosis. Odanacatib (ODN) is a nonbasic selective cathepsin K inhibitor with good pharmacokinetic parameters such as minimal in vitro metabolism, long half-life, and oral bioavailability. In preclinical studies, ovariectomized monkeys and rabbits treated with ODN showed substantial inhibition of bone resorption markers along with increases in bone mineral density (BMD). Significant differences were observed in the effects of ODN treatment compared with those of other antiresorptive agents such as bisphosphonates and denosumab. ODN displayed compartment-specific effects on trabecular versus cortical bone formation, with treatment resulting in marked increases in periosteal bone formation and cortical thickness in ovariectomized monkeys whereas trabecular bone formation was reduced. Furthermore, osteoclasts remained viable. Phase I and II studies conducted in postmenopausal women showed ODN to be safe and well tolerated. After 5 years, women who received ODN 50 mg weekly continuously from year 1 (n = 13), showed BMD increases from baseline of 11.9% at the lumbar spine, 9.8% at the femoral neck, 10.9% at the hip trochanter, and 8.5% at the total hip. Additionally, these subjects maintained a low level of the urine bone resorption marker N-terminal telopeptide/creatinine (-67.4% from baseline) through 5 years of treatment, while levels of serum bone-specific alkaline phosphatase remained only slightly reduced relative to baseline (-15.3%). In women who were switched from ODN to placebo after 2 years, bone turnover markers were transiently increased and BMD gains reversed after 12 months off medication. Adverse experiences in the ODN-treated group were not significantly different from the placebo group. In conclusion, available data suggests that cathepsin K inhibition could be a promising intervention with which to treat osteoporosis. Ongoing studies are expected to provide information on the long-term efficacy in fracture reduction and safety of prolonged treatment with ODN.

Topics: Animals; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Cathepsin K; Disease Models, Animal; Female; Humans; Macaca mulatta; Osteoporosis, Postmenopausal; Rabbits

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

This study aimed to investigate the inhibitory effect of Odanacatib on orthodontic recurrence in rats.. Forty rats were selected to establish a planting anchorage molar movement model, and 50 g of force was used for the mesial movement of the right maxillary first molar. Forty rats were randomly divided into the observation group (n=20) and control group (n=20). Odanacatib (60 μl, 1.25 μM) was locally injected into the mucoperiosteum around the right maxillary first molar of rats in the experimental group, and an equal amount of normal saline was injected into rats in the control group. A Vernier caliper was used for measuring the recurrence movement distance and recurrence rate of rats, Micro-CT for scanning the bone mineral density (BMD) and bone volume fraction (BVF) of the alveolar bone, TRAP special staining for observing changes in osteoclasts and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) for detecting the mRNA expressions of cathepsin K (CatK) and insulin-like growth factor 1 (IGF-1) in periodontal tissues.. After 3 weeks of modeling, the movement distance of the first molar of rats in the two groups was 1.16±0.19 mm. The molar movement distance and recurrence rate of rats were significantly higher in the control group than those in the observation group (p<0.05). The BMD and BVF of the alveolar bone of rats were markedly lower in the control group than those in the observation group (p<0.05). There was no statistically significant difference in the number of osteoclasts between the observation group (26.15±3.92) and the control group (27.01±2.74) (t=0.882, p=0.383). The CatK mRNA expression of rats was remarkably lower in the observation group than that in the control group (p<0.05). The IGF-1 mRNA expression of rats was significantly higher in the observation group than that in the control group (p<0.05).. By promoting the IGF-1 mRNA expression and increasing the BMD and BVF of the alveolar bone, Odanacatib inhibits orthodontic recurrence and has no effect on osteoclast activity.

Topics: Alveolar Process; Animals; Biphenyl Compounds; Cathepsin K; Disease Models, Animal; Insulin-Like Growth Factor I; Mesial Movement of Teeth; Osteoclasts; Periodontium; Rats, Inbred Strains; Recurrence; RNA, Messenger; Tooth Migration; Tooth Movement Techniques; X-Ray Microtomography

Topics: Absorptiometry, Photon; Animals; Biomarkers; Biomechanical Phenomena; Biphenyl Compounds; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Cancellous Bone; Cortical Bone; Disease Models, Animal; Female; Femur; Lumbar Vertebrae; Organ Size; Ovariectomy; Rabbits; Regression Analysis; Tomography, X-Ray Computed; Withholding Treatment

Periapical disease, an inflammatory disease mainly caused by dental caries, is one of the most prevalent infectious diseases of humans, affecting both children and adults. The infection travels through the root, leading to inflammation, bone destruction, and severe pain for the patient. Therefore, the development of a new class of anti-periapical disease therapies is necessary and critical for treatment and prevention. A small molecule, odanacatib (ODN), which is a cathepsin K (Ctsk) inhibitor, was investigated to determine its ability to treat this disease in a mouse model of periapical disease. While Ctsk was originally found in osteoclasts as an osteoclast-specific lysosomal protease, we were surprised to find that ODN can suppress the bacterium-induced immune response as well as bone destruction in the lesion area. X rays and microcomputed tomography (micro-CT) showed that ODN treatment had significant bone protection effects at different time points. Immunohistochemical and immunofluorescent staining show that ODN treatment dramatically decreased F4/80+ macrophages and CD3+ T cells in the lesion areas 42 days after infection. Consistent with these findings, quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis showed low levels of proinflammatory mRNAs (for tumor necrosis factor alpha, interleukin 6, and interleukin 23α) and corresponding cytokine expression in the ODN-treated disease group. The levels of mRNA for Toll-like receptors 4, 5, and 9 also largely decreased in the ODN-treated disease group. Our results demonstrated that ODN can inhibit endodontic disease development, bone erosion, and immune response. These results indicate that application of this small molecule offers a new opportunity to design effective therapies that could prevent periapical inflammation and revolutionize current treatment options.

Topics: Alveolar Bone Loss; Animals; Biphenyl Compounds; Cathepsin K; Dental Caries; Disease Models, Animal; Interleukin-23 Subunit p19; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred BALB C; Osteoclasts; Periapical Periodontitis; RNA, Messenger; T-Lymphocytes; Toll-Like Receptor 4; Toll-Like Receptor 5; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha

Periodontitis is a bacteria-induced inflammatory disease mainly affecting periodontal tissues, leading to periodontal inflammation, bone breakdown, and loss of the tooth. The main obstacle for treating periodontitis effectively is the difficulty in finding a target that can inhibit bone loss and inflammation simultaneously. Recent studies showed that cathepsin K (CTSK) might have functions in the immune system besides its role in osteoclasts. Thus, targeting CTSK would have a potential therapeutic effect in both the bone system and the immune system during the progression of periodontitis.. In the current study, a small molecular inhibitor (odanacatib [ODN]) is explored to inhibit the function of CTSK in a bacteria-induced periodontitis mouse model.. The application of ODN decreased the number of osteoclasts, macrophages, and T cells, as well as the expression of Toll-like receptors (TLRs) in the periodontitis lesion area. Furthermore, lack of CTSK inhibited the expression of TLR4, TLR5, and TLR9 and their downstream cytokine signaling in the gingival epithelial cells in periodontitis lesions, demonstrating that the innate immune response was inhibited in periodontitis.. The present results show that inhibition of CTSK can prevent bone loss and the immune response during the progression of periodontitis, indicating that CTSK is a promising target for treating inflammatory diseases such as periodontitis by affecting both osteoclasts and the immune system.

Topics: Alveolar Bone Loss; Animals; Anti-Inflammatory Agents; Bacteroidaceae Infections; Biphenyl Compounds; Cathepsin K; Disease Models, Animal; Epithelial Cells; Female; Gingiva; Gram-Negative Bacterial Infections; Immunity, Innate; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Osteoclasts; Periodontitis; Porphyromonas gingivalis; T-Lymphocytes; Tannerella forsythia; Toll-Like Receptor 4; Toll-Like Receptor 5; Toll-Like Receptor 9; Treponema denticola; Treponemal Infections

This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's.

Topics: Animals; Biomechanical Phenomena; Biphenyl Compounds; Bone Density; Cathepsin K; Cysteine Proteinase Inhibitors; Disease Models, Animal; Female; Finite Element Analysis; Humans; Macaca mulatta; Osteoporosis; Ovariectomy; X-Ray Microtomography