The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents

Abstract

The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.

Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

“…13,14 The first systemic pharmacokinetic study of small molecule perforin inhibitors revealed that the in vivo clearance of the studied inhibitors was very high as they were prone to phase I metabolic reactions, although the redoxmetabolism did not completely explain fast clearance. 15 Therefore, if the perforin inhibitors are rapidly cleared from the body, they may be unable to reach their target sites at therapeutically relevant concentrations. In addition, to reach their site of action, drugs intended for the treatment of central nervous system disorders have to cross the blood−brain barrier.…”

Perforin facilitates beta cell killing and regulates autoreactive CD8+ T‐cell responses to antigen in mouse models of type 1 diabetes

“…Our results indicate that the absence of perforin in CTLs is sufficient to protect NOD mice from autoimmune diabetes. This is important for potential translation to prevention of CTL‐mediated beta cell destruction in humans using perforin inhibitors 19 , 20 …”

“…This is important for potential translation to prevention of CTL-mediated beta cell destruction in humans using perforin inhibitors. 19,20 TCR transgenic NOD8.3 mice, in which beta cell destruction is dependent on CTLs, develop diabetes in the absence of perforin. 8 In contrast, perforin-deficient NOD mice, with a polyclonal CTL pool, have less diabetes and insulitis.…”

Spectral Characteristic and Preliminary Anticancer Activity in vitro of Selected Rhodanine‐3‐carboxylic Acids Derivatives

“…The similar activity is demonstrated by derivatives possessing a carboxymethylene group at N‐3 position and arylidene or heteroarylmethylidene group at C‐5 position . Furthermore, derivatives of another five‐membered system, containing exocyclic sulfur atom, possess similar biological properties . These compounds are based on 2‐thioxo‐4‐imidazolidinone system and are called thiohydantoins.…”