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 (1.79 L/kg), t (23.1 h) and CL (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 like plasma values. 7. LASSBio-1736 protein binding was 95 ± 2%. 8. The t, CL and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.

Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity

“…As shown in Tables 3 and 4 , both compounds showed high plasma and microsomal stability. These data agree with the previous information described by Moraes (2017) and Alves (2020), indicating that LASSBio-1736, despite its peptidomimetic nature, has a great stability in rat plasma [ 13 , 17 ]. The plasma half-life of LASSBio-1736 and LASSBio-1491 was 19.25 h and 28.87 h, respectively.…”

“…The data are important to determinate if a prototype will be able to reach target tissues in leishmaniasis, since liver is an important organ for leishmanicidal activity [ 41 , 42 ]. Pharmacokinetic characteristics such as long half-life, low systemic clearance and adequate liver penetration are desirable for leishmanicidal drugs, as reported by Moraes & colleagues [ 17 ] in in vivo studies with LASSBio-1736.…”

“…In this paper, we described the pre-clinical study of LASSBio-1491, a less lipophilic isostere of LASSBio-1736 ( Fig 1 ), bearing a 5-nitrofuran group, a common fragment used to explore antiprotozoal activity [ 14 – 17 ], aiming to compare their in vitro pharmacokinetic (PK) and to establish its antileishmanial activity in vitro and in vivo .…”