title: Lysophospholipid receptors in drug discovery.
abstract: Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field.
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, DNC-118, 10550 N, Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kihara
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, DNC-118, 10550 N, Torrey Pines Road, La Jolla, CA 92037, USA; Exploratory Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki 300-4247, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, DNC-118, 10550 N, Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jchun@scripps.edu.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology; D058990:Molecular Targeted Therapy; D009103:Multiple Sclerosis / Q000188:drug therapy; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000502:physiology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine; C032881:lysophosphatidic acid
keywords: Cannabinoids; FTY720; Fingolimod; GPCR; Idiopathic pulmonary fibrosis; LPA; LPS; Multiple sclerosis; S1P