title: Design, synthesis, and biological evaluation of novel thiazolidinediones as PPARγ/FFAR1 dual agonists.
abstract: Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPARγ is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPARγ and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Khaled M
authors.initials: KM
authors.lastname: Darwish
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Ismail
authors.initials: I
authors.lastname: Salama
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Mostafa
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. Electronic address: mohamed_hilal@pharm.suez.edu.eg.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Helal
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones
keywords: Diabetes; Docking; FFAR1; PPARγ; Thiazolidinedione