title: Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD.
abstract: Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target.
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London, UK SW7 2AZ.
authors.forename: Yushma
authors.initials: Y
authors.lastname: Bhurruth-Alcor
authors.forename: Therese
authors.initials: T
authors.lastname: Røst
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jorgensen
authors.forename: Christos
authors.initials: C
authors.lastname: Kontogiorgis
authors.forename: Jon
authors.initials: J
authors.lastname: Skorve
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooper
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sheridan
authors.forename: William D O
authors.initials: WD
authors.lastname: Hamilton
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Heal
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D012984:Software
chemical_list: D007211:Indoles; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma