Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities.

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.

• Authors: Elizabeth A Jurica, Ximao Wu, Kristin N Williams, Lauren E Haque, Richard A Rampulla, Arvind Mathur, Min Zhou, Gary Cao, Hong Cai, Tao Wang, Heng Liu, Carrie Xu, Lori K Kunselman, Thomas M Antrilli, Michael B Hicks, Qin Sun, Elizabeth A Dierks, Atsu Apedo, Douglas B Moore, Kimberly A Foster, Mary Ellen Cvijic, Reshma Panemangalore, Purnima Khandelwal, Jason J Wilkes, Bradley A Zinker, Donald G Robertson, Evan B Janovitz, Michael Galella, Yi-Xin Li, Julia Li, Thangeswaran Ramar, Prasada Rao Jalagam, Ramya Jayaram, Jean M Whaley, Joel C Barrish, Jeffrey A Robl, William R Ewing, Bruce A Ellsworth
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 85 Pg. 117273 (05 01 2023) ISSN: 1464-3391 [Electronic] England
• PMID: 37030194 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Blood Glucose
• Receptors, G-Protein-Coupled
• Glucagon-Like Peptide 1
• Hypoglycemic Agents
• Pyrrolidines
• Insulin

Topics

• Rats
• Animals
• Blood Glucose
• Receptors, G-Protein-Coupled
• Glucagon-Like Peptide 1
• Hypoglycemic Agents (pharmacology)
• Hyperglycemia
• Pyrrolidines (pharmacology, chemistry)
• Insulin