“…1 ). The results are consistent with a previous study, in which the IC 50 value of MIV-711 in a bone resorption assay using differentiated human osteoclasts incubated together with bovine bone slices was 37 nmol/L [ 25 ] (note: MIV-711 was referred to as MV076159 in that publication). Fig.…”
Section: Resultssupporting
confidence: 92%
“…MIV-711 displayed high potency against recombinant human cathepsin K enzyme (K i : 0.98 nmol/L) and inhibited human osteoclast-mediated bone resorption with an IC 50 of 43 nmol/L. The observation that concentrations of MIV-711, which has a pKa value of 7.15, need to be around 50-fold higher than the K i value to show effects on bone resorption in vitro is consistent with previous data [ 25 ].…”
Section: Discussionsupporting
confidence: 90%
“…The batches of MIV-711 (previously referred to as MV076159; [ 25 ]) used in nonclinical experiments were synthesized at Medivir (Huddinge, Sweden). In all nonclinical experiments in vivo, MIV-711 was suspended in 1% w/v methyl cellulose (Methocel 4AC premium, Sigma) and given as a suspension via oral gavage.…”
BackgroundCathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man.MethodsThe potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3–30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg.ResultsMIV-711 was a potent inhibitor of human cathepsin K (Ki: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data.ConclusionsMIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA.Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011
“…1 ). The results are consistent with a previous study, in which the IC 50 value of MIV-711 in a bone resorption assay using differentiated human osteoclasts incubated together with bovine bone slices was 37 nmol/L [ 25 ] (note: MIV-711 was referred to as MV076159 in that publication). Fig.…”
Section: Resultssupporting
confidence: 92%
“…MIV-711 displayed high potency against recombinant human cathepsin K enzyme (K i : 0.98 nmol/L) and inhibited human osteoclast-mediated bone resorption with an IC 50 of 43 nmol/L. The observation that concentrations of MIV-711, which has a pKa value of 7.15, need to be around 50-fold higher than the K i value to show effects on bone resorption in vitro is consistent with previous data [ 25 ].…”
Section: Discussionsupporting
confidence: 90%
“…The batches of MIV-711 (previously referred to as MV076159; [ 25 ]) used in nonclinical experiments were synthesized at Medivir (Huddinge, Sweden). In all nonclinical experiments in vivo, MIV-711 was suspended in 1% w/v methyl cellulose (Methocel 4AC premium, Sigma) and given as a suspension via oral gavage.…”
BackgroundCathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man.MethodsThe potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3–30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg.ResultsMIV-711 was a potent inhibitor of human cathepsin K (Ki: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data.ConclusionsMIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA.Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011
“…Lysosomal accumulation of drugs may be responsible for cross-inhibition of multiple cathepsins, in various tissues, leading to extraskeletal adverse events [Duong, 2012]. Basic compounds are more potent than nonbasic compounds in suppressing osteoclastic bone resorption [Fuller et al 2010] for a longer duration, without effect on selectivity of the CatK inhibition.…”
Section: What Is a Cathepsin K Inhibitor?mentioning
Odanacatib is a cathepsin K inhibitor developed for the treatment of postmenopausal osteoporosis. It is a bone resorption inhibitor, but which preserves bone formation to some extent. It can be administered once a week, in tablets also containing vitamin D. In a large clinical development program, it has been shown that odanacatib reduces bone resorption, with a reduction of about 60-70% in biochemical markers of resorption, while bone formation decreases to a lesser magnitude. Odanacatib continuously increases bone mineral density (BMD) at the hip and lumbar spine over 5 years. Once it is stopped, a complete resolution of effect is observed, with declining BMD and increased bone turnover. Bone microarchitecture and bone strength have also been improved in clinical trials using quantitative computed tomography (QCT) at the lumbar spine and hip, and high resolution peripheral QCT at the distal radius and tibia. In a phase III trial involving 16,713 postmenopausal women ⩾65 years of age with low BMD, the risk of fragility fracture was significantly reduced at the spine, hip and other nonvertebral sites compared with the placebo group. Odanacatib has been generally well tolerated, with no observation of osteonecrosis of the jaw so far, but with exceptional observations of subtrochanteric atypical fracture and morphea-like lesions. Odanacatib appears a useful new option in the treatment of postmenopausal osteoporosis.
“…Phase I and II trials conducted in postmenopausal women showed that ODN to be safe and well tolerated [ 14 ]. Although developed as antiresorptive agents, several compounds show lysosomotropic effects [ 16 ], cutaneous adverse effects and anabolic activity [ 18 ], which are intrinsically related to the selectivity of inhibitors toward CatK. Therefore, alternative compounds having better selectivity toward CatK may complement the use of CKIs in bone resorption therapy.…”
AimThe cysteine protease cathepsin K (CatK), abundantly expressed in osteoclasts, is responsible for the degradation of bone matrix proteins, including collagen type 1. Thus, CatK is an attractive target for new anti-resorptive osteoporosis therapies, but the wider effects of CatK inhibitors on bone cells also need to be evaluated to assess their effects on bone. Therefore, we selected, among a series of synthetized isothiosemicarbazides, two molecules which are highly selective CatK inhibitors (CKIs) to test their effects on osteoblasts and osteoclasts.Research Design and MethodsCell viability upon treatment of CKIs were was assayed on human osteoblast-like Saos-2, mouse monocyte cell line RAW 264.7 and mature mouse osteoclasts differentiated from bone marrow. Osteoblast-induced mineralization in Saos-2 cells and in mouse primary osteoblasts from calvaria, with or without CKIs,; were was monitored by Alizarin Red staining and alkaline phosphatase activity, while osteoclast-induced bone resorption was performed on bovine slices.ResultsTreatments with two CKIs, CKI-8 and CKI-13 in human osteoblast-like Saos-2, murine RAW 264.7 macrophages stimulated with RANKL and mouse osteoclasts differentiated from bone marrow stimulated with RANKL and MCSF were found not to be toxic at doses of up to 100 nM. As probed by Alizarin Red staining, CKI-8 did not inhibit osteoblast-induced mineralization in mouse primary osteoblasts as well as in osteoblast-like Saos-2 cells. However, CKI-13 led to a reduction in mineralization of around 40% at 10–100 nM concentrations in osteoblast-like Saos-2 cells while it did not in primary cells. After a 48-hour incubation, both CKI-8 and CKI-13 decreased bone resorption on bovine bone slices. CKI-13 was more efficient than the commercial inhibitor E-64 in inhibiting bone resorption induced by osteoclasts on bovine bone slices. Both CKI-8 and CKI-13 created smaller bone resorption pits on bovine bone slices, suggesting that the mobility of osteoclasts was slowed down by the addition of CKI-8 and CKI-13.Conclusion
CKI-8 and CKI-13 screened here show promise as antiresorptive osteoporosis therapeutics but some off target effects on osteoblasts were found with CKI-13.
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