title: Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835.
abstract: A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC50= 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.
authors.affiliation: Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation. Electronic address: m.krasavin@spbu.ru.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
authors.affiliation: Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow, 117571 Russian Federation.
authors.forename: Alexey
authors.initials: A
authors.lastname: Lukin
authors.affiliation: Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow, 117571 Russian Federation.
authors.forename: Daria
authors.initials: D
authors.lastname: Bagnyukova
authors.affiliation: Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow, 117571 Russian Federation.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Zhurilo
authors.affiliation: Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow, 117571 Russian Federation.
authors.forename: Aleksei
authors.initials: A
authors.lastname: Golovanov
authors.affiliation: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine; Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zozulya
authors.affiliation: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine.
authors.forename: Ihor
authors.initials: I
authors.lastname: Zahanich
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moore
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
mesh_terms: D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry*; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; C000614377:LY2881835; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D013141:Spiro Compounds
keywords: Antidiabetic agents; Drug discovery; FFA1 agonists; Hydrophobic interactions; Spirocyclic motifs; π−π stacking