Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities. (1st May 2023)

• Record Type: Journal Article
• Authors: Jurica, Elizabeth A.; Wu, Ximao; Williams, Kristin N.; Haque, Lauren E.; Rampulla, Richard A.; Mathur, Arvind; Zhou, Min; Cao, Gary; Cai, Hong; Wang, Tao; Liu, Heng; Xu, Carrie; Kunselman, Lori K.; Antrilli, Thomas M.; Hicks, Michael B.; Sun, Qin; Dierks, Elizabeth A.; Apedo, Atsu; Moore, Douglas B.; Foster, Kimberly A.; Cvijic, Mary Ellen; Panemangalore, Reshma; Khandelwal, Purnima; Wilkes, Jason J.; Zinker, Bradley A.; Robertson, Donald G.; Janovitz, Evan B.; Galella, Michael; Li, Yi-Xin; Li, Julia; Ramar, Thangeswaran; Jalagam, Prasada Rao; Jayaram, Ramya; Whaley, Jean M.; Barrish, Joel C.; Robl, Jeffrey A.; Ewing, William R.; Ellsworth, Bruce A.;
• Is Part Of: Bioorganic & medicinal chemistry. Volume 85(2023)
• Publication Date: 2023-05-01
• Subjects: GPR40 -- FFAR1 -- GLP-1 -- Type 2 diabetes -- AgoPAM -- Pyrrolidine -- Hyperglycemia -- Saturation -- Chirality -- Polarity; GPR40 free fatty acid receptor 1 -- GPCR G-protein-coupled receptor -- GLP-1 glucagon-like peptide-1 -- T2DM type 2 diabetes mellitus -- AgoPAMs agonists that act as positive allosteric modulators -- Fsp3 fraction sp3 -- hGPR40 human GPR40 receptor -- mGPR40 mouse GPR40 receptor -- SAR structure activity relationship -- CHO Chinese hamster ovary -- FLIPR fluorescent imaging plate reader -- HEK human embryonic kidney -- PPARγ peroxisome proliferator-activated receptor gamma -- EC50 half maximal effective concentration -- cAMP cyclic adenosine monophosphate -- GSH glutathione -- CYP cytochrome P450 -- AUC area under the curve -- PK pharmacokinetic -- SD Sprague – Dawley -- SFC supercritical fluid chromatography -- DPP4 dipeptidyl peptidase 4 -- OGTT oral glucose tolerance test -- MDCK Madin-Darby canine kidney; 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.2023.117273
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.