A Selective Adenosine A 3 Receptor Antagonist, HL3501, Has Therapeutic Potential in Preclinical Liver and Renal Fibrosis Models.

Autor: Kim Y; Handok Inc., Seoul, Republic of Korea.; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea., Kim DM; Handok Inc., Seoul, Republic of Korea., Son WC; Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea wcson@amc.seoul.kr byounggon.moon@handok.com., Moon BG; Handok Inc., Seoul, Republic of Korea; wcson@amc.seoul.kr byounggon.moon@handok.com.
Jazyk: angličtina
Zdroj: In vivo (Athens, Greece) [In Vivo] 2022 Sep-Oct; Vol. 36 (5), pp. 2186-2193.
DOI: 10.21873/invivo.12944
Abstrakt: Background/aim: Adenosine and 4 G-protein-associated membrane receptors (A 1 , A 2A , A 2B , and A 3 ) and their derivatives regulate the central nervous, cardiovascular, peripheral, and immune system. We developed a novel selective A 3 AR antagonist, HL3501, and examined its anti-fibrotic effects across various models.
Materials and Methods: The anti-fibrotic activity of HL3501 was evaluated in three cell lines (HK2, LX2, and Primary hepatic stellate cell) and a methionine-choline-deficient (MCD) model including use of mouse pharmacokinetics (PK).
Results: HL3501 decreased alpha-smooth muscle actin (α-SMA) and collagen 1 in TGF-β1-induced pro-fibrotic activation in HK2 cells. HL3501 also inhibited TGF-β1-induced HSC activation, which resulted in reduction of α-SMA and fibronectin in LX2 and human primary HSCs. In the nonalcoholic fatty liver disease activity score (NAS) analysis, HL3501 showed improved anti-steatosis and anti-inflammatory activity. The mouse PK study revealed the oral bioavailability (%F) of HL3501 at 30 mg/kg and 60 mg/kg as 92.5 and 107.2%, respectively.
Conclusion: HL3501 presents anti-fibrotic effects in in vitro and in vivo studies. We also demonstrated that HL3501 is orally available and has a good bioavailability (BA >90%) profile from in mouse PK. HL3501, therefore, has a therapeutic potential for various fibrotic diseases, including those of liver and kidney tissues.
(Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
Databáze: MEDLINE
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