VEL-0230

Cathepsin K is highly expressed in osteoclasts and plays an essential role in bone resorption. NC-2300 is an artificially designed cathepsin K inhibitor, and its application to experimentally induced arthritis induces down-regulation of bone destruction. In this study, we evaluated the effects of NC-2300 on inflammation and bone destruction in experimentally induced rat periapical lesions.

The dental pulps of lower first molars in rats were extirpated, and the pulp chambers were left open to the oral environment. NC-2300 and phosphate-buffered saline were administered orally twice a day in the experimental and control groups, respectively. Animals were sacrificed on day 21, and the mandibles were extracted. The left hemimandibles were used for micro-computed tomographic and histologic examination. For the right hemimandibles, RNA was extracted from the periapical tissues surrounding the root apices, and inflammatory mediator expression was examined by real-time polymerase chain reaction using complementary DNA converted from extracted RNA.

The size of the periapical lesion, number of tartrate-resistant acid phosphatase-positive osteoclasts and major histocompatibility complex class II molecule-expressing macrophages in the experimental group decreased significantly when compared with the control group. The expression of proinflammatory cytokines in the experimental group was significantly suppressed when compared with the control group.

These results suggest that the cathepsin K inhibitor may inhibit not only cathepsin K activity in osteoclasts but also inflammatory mediator synthesis relating to osteoclastogenesis, and these synergistic effects may be involved in the suppression of periapical lesion expansion.

Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy‐terminal cross‐linking telopeptide of type I collagen (CTX‐1)] analyses were performed following single and multiple oral dose protocols of a Cathepsin K inhibitor (VEL‐0230) in horses. Outcomes included plasma and urine drug and CTX‐1 concentrations. In the dose range study, 2, 4, and 8 mg/kg body weight (b.w.) doses were administered in a Latin square design to three mares and evaluated for 1 week. Based on the PK characteristics of VEL‐0230, 4 mg/kg b.w. was selected for the dose interval study in which 3.25 days (d) and 7 days dose intervals were evaluated over three administrations using four exercising horses in a Latin square design. The 3.25 days and 7 days dose intervals provided a rapid inhibition of bone resorption based on plasma CTX‐1. CTX‐1 inhibition prior to next dose administration was not different from baseline in the 3.25 days and 7 days protocols, and for the first 3 days but the sustained CTX‐1 inhibition in the 7 days protocol along with the cost and logistic benefits for weekly administration made the 7 days protocol preferable. Weekly administration of VEL‐0230 may provide effective inhibition of bone resorption in young exercising horses that returns to baseline within 7 days after drug withdrawal even after multiple doses.