title: Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40).
abstract: A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved.
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; Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, 1 Murmanska, Kyiv 02660, Ukraine.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kondratov
authors.affiliation: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine; Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Naumchyk
authors.affiliation: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kheylik
authors.affiliation: Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine.
authors.forename: Maxim
authors.initials: M
authors.lastname: Platonov
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: Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation. Electronic address: m.krasavin@spbu.ru.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
mesh_terms: D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008744:Methylamines / Q000737:chemistry; D051379:Mice; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011422:Propionates / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C473034:FFAR1 protein, human; C515630:GW9508; D008744:Methylamines; D010069:Oxadiazoles; D010080:Oxazoles; D011422:Propionates; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D003577:Cytochrome P-450 Enzyme System
keywords: ADME profile; Agonists; Anti-diabetic agents; Cytochrome inhibition; Free fatty acid receptor agonists; Glucose-stimulated insulin secretion; Hit expansion; Hypoglycemia