SID 26681509

SID 26681509 is a potent, reversible, competitive, and selective inhibitor of human cathepsin L with an IC₅₀ of 56 nM. SID 26681509 inhibits in vitro propagation of malaria parasite Plasmodium falciparum and inhibits Leishmania major with IC₅₀s of 15.4 μM and 12.5 μM, respectively. SID 26681509 shows no inhibitory activity against cathepsin G^[1]. IC50 & Target:IC50: 56 nM (Human cathepsin L), 0.5 μM (Cathepsin V), 15.4 μM (Plasmodium falciparum), 12.5 μM (Leishmania major)^[1] In Vitro: After a 4 hr preincubation with cathepsin L, SID 26681509 becomes more potent, demonstrating an IC₅₀ of 1.0 nM. SID 26681509 is determined to be a slow-binding and slowly reversible competitive inhibitor. Through a transient kinetic analysis for single-step reversibility, inhibition rate constants are kon = 24,000 M^-1s^-1 and koff = 2.2 × 10^-5 s^-1 (K_i = 0.89 nM). Molecular docking studies are undertaken using the experimentally-derived X-ray crystal structure of papain/CLIK-148^[1].
SID 26681509 inhibits papain and cathepsins B, K, S, and V with IC₅₀ values determined after one hour ranging from 618 nM to 8.442 μM. SID 26681509 shows no inhibitory activity against the serine protease cathepsin G^[1].
SID 26681509 inhibits cathepsin V activity with an IC₅₀ value of 0.5 μM. SID 26681509 (1-30 μM) blocks high-mobility group box 1 (HMGB1)-induced TNF-α production dose dependently without altering cell viability^[2]. In Vivo: SID 26681509 treatment significantly improves survival in murine models of sepsis and reduces liver damage following warm liver ischemia/reperfusion (I/R) models^[2].