Discovery of Palindrome Dual PPARγ‐GPR40 Agonists for Treating Type 2 Diabetes

• Published in: ChemMedChem Vol. 19; no. 24; pp. e202400492 - n/a
• Main Authors: Rodríguez‐Luévano, Ana, Almanza‐Pérez, Julio C., Ortiz‐Andrade, Rolffy, Lara‐González, Samuel, Santillán, Rosa, Navarrete‐Vázquez, Gabriel, Giacoman‐Martínez, Abraham, Lazzarini‐Lechuga, Roberto C., Bautista, Elihú, Hidalgo‐Figueroa, Sergio
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 16.12.2024
• Subjects: Agonists; Animal models; Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell culture; Chemical compounds; Chemical reactions; Chemical synthesis; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Gene expression; Glucose; Glucose Transporter Type 4 - metabolism; GPR40; Humans; Hypoglycemia; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; In vivo methods and tests; Insulin; Insulin secretion; Male; Molecular Docking Simulation; Molecular dynamics; Molecular Structure; Palindromic design; Peroxisome proliferator-activated receptors; Pioglitazone; PPAR gamma - agonists; PPAR gamma - metabolism; PPARγ; Rats; Receptors; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Structure-Activity Relationship; Translocation; Palindromic design; Molecular dynamics; Diabetes; GPR40; PPARγ
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202400492

This work describes a first attempt of palindromic design for dual compounds that act simultaneously on peroxisome proliferator‐activated receptor gamma (PPARγ) and G‐protein‐coupled receptor 40 (GPR40) for the treatment of type 2 diabetes. The compounds were synthesized by multi‐step chemical reactions and the relative mRNA expression levels of PPARγ, GPR40, and GLUT‐4 were measured in cultured C2 C12 muscle cells and RIN‐m5 f β‐pancreatic cells. In addition, insulin secretion and GLUT‐4 translocation were measured. Compound 2 displayed a moderate increase in the mRNA expression of PPARγ and GPR40. However, the translocation of the GLUT‐4 transporter was 400 % with a similar effect to pioglitazone. The in vivo effect of compound 2 was determined at 25 mg/kg single dose using a normoglycemic and non‐insulin dependent diabetes mellitus (NIDDM) rat models. Compound 2 showed basal plasma glucose in diabetic rats with feed intake, which is associated with the moderate release of insulin measured in cells. Surprisingly, the glucose does not decrease in normoglycemic rats. Compound 2 maintained significant interactions with the GPR40 and PPARγ receptors during molecular dynamics. Altogether, the results demonstrate that compound 2, with a palindromic design, simultaneously activates PPARγ and GPR40 receptors without inducing hypoglycemia. A new prototype of palindromic dual PPARγ‐GPR40 agonists has been developed to simultaneously activate both receptors. The results have successfully established a novel concept for drug design and it can be used to develop new drugs. This work focuses on chemical synthesis, pharmacological activity (in vitro and in vivo), and computational approaches.