Identification of potent lysophosphatidic acid receptor 5 (LPA5) antagonists as potential analgesic agents

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 1; pp. 257 - 265
• Main Authors: Kawamoto, Yuichiro, Seo, Ryushi, Murai, Nobuhito, Hiyama, Hideki, Oka, Hiromasa
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2018; Elsevier
• Subjects: Analgesic agents; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; BBB permeability; Biochemistry & Molecular Biology; Blood-Brain Barrier - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chronic Disease; CNS MPO score; Constriction, Pathologic - drug therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Homology model; Humans; Life Sciences & Biomedicine; LPA5 antagonist; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Rats; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; Homology model; CNS MPO score; BBB permeability; Analgesic agents; LPA5 antagonist; BENZENE; PAIN; RAT; DISORDERS; STACKING INTERACTIONS; GPR92; LPA
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.11.038

[Display omitted] 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.