| Literature DB >> 29208511 |
Yuichiro Kawamoto1, Ryushi Seo2, Nobuhito Murai2, Hideki Hiyama2, Hiromasa Oka3.
Abstract
Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC50 value of 0.12 μM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach.Entities:
Keywords: Analgesic agents; BBB permeability; CNS MPO score; Homology model; LPA5 antagonist
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Year: 2017 PMID： 29208511 DOI： 10.1016/j.bmc.2017.11.038
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641