N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Hoveyda, Hamid R.; Fraser, Graeme L.; Zoute, Ludivine; Dutheuil, Guillaume; Schils, Didier; Brantis, Cyrille; Lapin, Alexey; Parcq, Julien; Guitard, Sandra; Lenoir, François; Bousmaqui, Mohamed El; Rorive, Sarah; Hospied, Sandrine; Blanc, Sébastien; Bernard, Jérôme; Ooms, Frédéric; McNelis, Joanne C.; Olefsky, Jerrold M.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 18(2018)
• Page Start: 5169
• Page End: 5180
• Publication Date: 2018-10-01
• Subjects: AUCu unbound area-under-the-curve -- (S)-BINAP (S)-(-)-(1, 1′-binaphthalene-2, 2′-diyl)bis(diphenylphosphine) -- CLu unbound systemic clearance rate -- Compd compound -- DIEA N, N-diisopropyl ethylamine, EtOAc, ethyl acetate -- FFA2 receptor free fatty acid-2 receptor -- Fsp3 fraction sp3 = number of sp3 hybridized carbons/total carbon count -- GPCR G-protein coupled receptor -- GTP- γ 35S guanosine 5′-O-[gamma-thio]triphosphate -- KO knock-out mice model -- HATU N-[(Dimethylamino)-1H-1, 2, 3-triazolo-[4, 5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide -- HTS high-throughput screening -- NMM N-methyl morpholine -- OGTT oral glucose tolerance test -- POC proof-of-concept -- PK pharmacokinetics -- SAR structure-activity relationship -- T1/2 elimination half-life; FFA2 agonist -- GPR43 agonist -- GPCR -- OGTT -- LLE -- Fsp3; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.09.015
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N -thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp 3 content (Fsp 3 ) parameters guided these efforts. Compound10 was advanced into studies in mice on the basis of its optimized profile vs initial lead1 (ΔLLE = 0.3, ΔFsp 3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.