Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution

Abstract

1. LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor.

2. This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats.

3. LASSBio-1736 was administered to male Wistar rats at doses of 3.2 mg/kg intravenously and 12.6 mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2 mg/kg drug by non-compartmental approach.

4. After intravenous administration, Vd_ss (1.79 L/kg), t _½ (23.1 h) and CL_tot (56.1 mL/h/kg) were determined, and they were statistically similar (α =0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption.

5. The intraperitoneal and oral bioavailability were around 40 and 15%, respectively.

6. Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t _½ like plasma values.

7. LASSBio-1736 protein binding was 95 ± 2%.

8. The t _½, CL_tot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.

Keywords:

• Cysteine protease inhibitor
• LASSBio-1736
• leishmaniasis
• leishmanicidal activity
• preclinical pharmacokinetics