title: Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity.
abstract: We report the pharmacophore of the peroxisome proliferator-activated receptor δ (PPARδ) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARδ agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Nihar
authors.initials: N
authors.lastname: Kinarivala
authors.affiliation: The Methodist Hospital Research Institute, Genomic Medicine Program, Houston, TX 77030, USA.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Mina
authors.initials: M
authors.lastname: Botros
authors.affiliation: The Methodist Hospital Research Institute, Genomic Medicine Program, Houston, TX 77030, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Center for Chemical Biology, Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA. Electronic address: paul.trippier@ttuhsc.edu.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trippier
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D006847:Hydrocarbons, Iodinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D053279:Polyynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006847:Hydrocarbons, Iodinated; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D047494:PPAR delta; D048068:PPAR-beta; C581059:phosphoiodyn A; D053279:Polyynes
keywords: Neurodegeneration; Neuroprotection; PPAR agonist; Pharmacophore identification