title: Novel agonists of free fatty acid receptor 1 (GPR40) based on 3-(1,3,4-thiadiazol-2-yl)propanoic acid scaffold.
abstract: 1,3,4-Thiadiazole was explored as a more polar, heterocyclic replacement for the phenyl ring in the 3-arylpropionic acid pharmacophore present in the majority of GPR40 agonists. Out of 13 compounds synthesized using a flexible, three-step protocol (involving no chromatographic purification), four compounds were confirmed to activate the target in micromolar concentration range. While the potency of the series should be subject of further optimization, the remarkable aqueous solubility and microsomal stability observed for the lead compound (8g) apparently attests to this new scaffold's high promise in the GPR40 agonist field.
authors.affiliation: a Department of Organic Chemistry , Institutes of Chemistry and Translational Biomedicine, Saint Petersburg State University , Saint Petersburg , Russian Federation .
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
authors.affiliation: b Lomonosov Moscow State Institute of Fine Chemical Technologies (MITHT) , Moscow , Russian Federation .
authors.forename: Alexey
authors.initials: A
authors.lastname: Lukin
authors.affiliation: b Lomonosov Moscow State Institute of Fine Chemical Technologies (MITHT) , Moscow , Russian Federation .
authors.forename: Nikolay
authors.initials: N
authors.lastname: Zhurilo
authors.affiliation: b Lomonosov Moscow State Institute of Fine Chemical Technologies (MITHT) , Moscow , Russian Federation .
authors.forename: Alexey
authors.initials: A
authors.lastname: Kovalenko
authors.affiliation: c Enamine Ltd , 78 Chervonotkatska, Kyiv , Ukraine , and.
authors.forename: Ihor
authors.initials: I
authors.lastname: Zahanich
authors.affiliation: c Enamine Ltd , 78 Chervonotkatska, Kyiv , Ukraine , and.|d Taras Shevchenko National University , 62 Volodymyrska, Kyiv , Ukraine.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zozulya
mesh_terms: D006801:Humans; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013057:Spectrum Analysis / Q000379:methods; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: C473034:FFAR1 protein, human; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole
keywords: Agonists; GPR40; aqueous solubility; bioisosteric replacement; cLogP; free fatty acid receptor 1; metabolic stability; total polar surface area