title: Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835.
abstract: The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.
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: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine.
authors.forename: Ihor
authors.initials: I
authors.lastname: Zahanich
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: School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Ihalainen
authors.affiliation: School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
authors.affiliation: School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.affiliation: School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
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: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C473034:FFAR1 protein, human; C000614377:LY2881835; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D013141:Spiro Compounds
keywords: FFA1 agonists; Free fatty acid receptor 1; GPCR; GPR40; Metabolic stability; Prins reaction; Spirocyclic motifs; Type 2 diabetes mellitus