Relacatib (SB-462795) is a novel, potent, and orally active inhibitor of human cathepsins K, L, and V. It exhibits high affinity for these enzymes, with Ki values of 41 pM, 68 pM, and 53 pM, respectively. Moreover, Relacatib effectively inhibits endogenous cathepsin K in situ in human osteoclasts, as well as human osteoclast-mediated bone resorption, with IC 50 values of 45 nM and 70 nM, respectively. Additionally, in vitro studies demonstrate Relacatib's inhibitory effect on bone resorption in human tissue, while in vivo studies on cynomolgus monkeys further validate its efficacy in reducing bone resorption.

Cathepsin K:41 pM (Ki), Cathepsin V:53 pM , Cathepsin L:68 pM

Relacatib are incubated with human osteoclastoma-derived osteoclasts seeded onto bovine cortical bone slices in vitro biological activity, it shows inhibitory potency with K i values of 0.041 nM, 0.068 nM,0.063 nM,1.6 nM,and 13 nM against human cathepsin K, cathepsin L, cathepsin V, cathepsin S and cathepsin B, respectively in the assay[1].

Relacatib is against Monkey cathepsin K, cathepsin L,cathepsin V and cathepsin B with K i values of 0.041 nM, 0.28 nM, 0.72 nM and 11nM, respectively. Relacatib is against mouse cathepsin L and rat cathepsin L with K i values of 0.20 nM and 0.17 nM, respectively[2].

Relacatib (1-2 mg/kg 0.5 h intravenous infusion; 2-4 mg/kg oral bolus gavage) exhibits T 1/2 , CL or V dss with 109 mins, 19.5 mL/min/kg, or 1.86 L/kg in male Sprague-Dawley rats and 168 mins, 11.7 mL/min/kg, and 1.79 L/kg in monkeys, respectively in a PK iv/po crossover studies. The oral bioavailability of Relacatib is 28% in the monkey and 89.4% in the rats[1].SB-462795 (subcutaneous injection; 12 mg/kg; blood sample is drawn 1.5, 4, 24, 48, and 72 h post dose administration) significantly inhibits resorption as assessed by two markers of bone resorption,the N- (NTx) and C-telopeptides (CTx) of type I collagen measured in serum. SB-462795 does not exhibit difference of serum osteocalcin (a biomarker of osteoblast activity) between SB-462795 and vehicle treated animalsexcept for the 48 h time point where a significant reduction (42% lower than baseline vs. 18% lower than baseline with vehicle treatment)[2]. Animal Model: Cynomolgus monkey[2]Dosage: 12 mg/kg Administration: Subcutaneous injection; single dose; blood sample is drawn 1.5, 4, 24, 48, and 72 h post dose administration Result: Was sufficiently high to significantly suppress bone resorption from 1.5 to 72 h post dosing.