Targeting the LPA1 signaling pathway for fibrosis therapy: a patent review (2010-present)

ABSTRACTABSTRACTIntroduction Fibrosis is a disease that damages organs and even causes death. Because of the complicated pathogenesis, the development of drugs for fibrosis is challenging. In the lysophosphatidic acid receptor type 1 (LPA1) signaling pathway, LPA1 and its downstream Rho-associated coiled-coil forming protein kinase (ROCK) are related to the process of fibrosis. Targeting LPA1 signaling pathway is a potential strategy for the treatment of fibrosis.Area covered This review describes the process of fibrosis mediated by the LPA1 signaling pathway and then summarizes LPA1 antagonist patents reported since 2010 and ROCK inhibitor patents since 2017 according to their scaffolds based on the Cortellis Drug Discovery Intelligence database. Information on LPA1 antagonists entering clinical trials is integrated.Expert opinion Over the past decade, a large number of antagonists targeting the LPA1 signaling pathway have been patented for fibrosis therapy. A limited number of compounds have entered clinical trials. Different companies and research groups have used different scaffolds when designing compounds for fibrosis therapy. Therefore, LPA1 and ROCK are competitive targets for the development of new therapies for fibrosis to provide a potential treatment method for fibrosis in the future.KEYWORDS: fibrosisLPA1 signaling pathwayLPA1 antagonistsROCK inhibitorspatent review Article highlights LPA1 is expressed at high levels in the process of fibrosis, and the degree of fibrosis may be alleviated by knocking out or antagonizing LPA1.The LPA1 signaling pathway is closely related to the process of fibrosis. Antagonists of LPA1 with various scaffolds exert antifibrotic effects.ROCK downstream of LPA1 causes cytoskeletal reorganization, regulates downstream fibrosis-related targets, such as CTGF, MMP and NF-κB, and then affects the process of fibrosis. Therefore, inhibitors targeting ROCK also treat fibrosis.Patents disclose LPA1 antagonists and ROCK inhibitors. Some leads have also entered clinical trials.Due to the wide distribution of LPA1 and ROCK, off-target effects cause adverse reactions. Drug structures were modified to reduce adverse reactions and improve physical and chemical properties.This box summarizes key points contained in the article.Declaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis study was supported by Projects 81903439 of the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province of China (no. BK20190562).