In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

Abstract

Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, <i>in vitro</i> liver microsomal stability and an <i>in vivo</i> pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and <i>in vitro</i> pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For <i>in vivo</i> pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (P<sub>app</sub>; 9.7×10<sup>–6</sup> cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t<sub>1/2</sub>) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and C<sub>max</sub> after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

Folic acid deficiency exacerbates the inflammatory response of astrocytes after ischemia‐reperfusion by enhancing the interaction between IL‐6 and JAK‐1/pSTAT3

“…The model of folic acid deficient primary astrocytes was established through folic acid deficient Dulbecco's modified eagle's medium (0 mg folic acid; Sigma) supplemented with 10% FBS. LMT‐28 (IL‐6 inhibitor, 30 μM), 17 C188‐9 (STAT3 inhibitor, 30 μM), 18 Filgotinib (a specific JAK‐1 inhibitor, 10 nM), and AG490 (a specific JAK‐2 inhibitor, 50 μM) 19 , 20 , 21 were used to inhibit the expression of the corresponding proteins.…”

Antibody-Mediated Screening of Peptide Inhibitors for Monoamine Oxidase-B (MAO-B) from an Autodisplayed FV Library

“…As an internal standard, angiotensin II (1046 Da) at a concentration of 5 μM was mixed with standard samples. The metabolic half-life time ( t 1/2 ), which represented the time to reach the half of initial concentration, was estimated using the following equation: , where k represents the elimination constant, which meant the amount of analyte eliminated in the liver microsomal metabolic reaction per unit time.…”

“…As an internal standard, angiotensin II (1046 Da) at a concentration of 5 μM was mixed with standard samples. The metabolic half-life time (t 1/2 ), which represented the time to reach the half of initial concentration, was estimated using the following equation: 32,34…”

The role of inflammation in autoimmune disease: a therapeutic target

“…LMT-28, an oxazolidinone derivative, was screened by HepG2 cells transfected with IL-6 stimulation of p-STAT3-Luc, and inhibited the action of IL-6 by targeting gp130 homodimers, with high activity (IC 50 = 5.9 μM, Kd = 7.4 μM) and low cytotoxicity, and had good pharmacokinetic characteristics ( 262 , 263 ). In CIA and acute pancreatitis models, LMT-28 exerted a therapeutic effect on arthritis and pancreatitis, decreased arthritis scores, and reduced expression of pro-inflammatory factors to exert anti-inflammatory activity ( 263 ).…”