Discovery of new dual PPARγ-GPR40 agonists with robust antidiabetic activity: Design, synthesis and in combo drug evaluation.
The design of compounds 1 and 2 was based on the similar scaffold of pharmacophoric groups for PPARγ and GPR40 agonists. In order to find new compounds with improved biological activity, the current manuscript describes a new dual PPARγ-GPR40 agonist. We synthesized two compounds, which were prepared following a multistep synthetic route, and the relative mRNA expression levels of PPARγ, GLUT4, and GPR40 were quantified in cell culture, as well as insulin secretion and [Ca2+] intracellular levels. Compound 1 showed a 7-times increase in the mRNA expression of PPARγ, which in turn enhanced the expression levels of GLUT4 respect to control and pioglitazone. It also showed an increase of 2-fold in the [Ca2+]ilevel allowing an increment on insulin release, being as active as the positive control (glibenclamide), causing also an increase of 2-fold in mRNA expression of GPR40. Furthermore, the compound 2 showed lower activity than the compound 1. The ester of 1 showed antidiabetic activity at a 50mg/kg single dose in streptozotocin-nicotinamide-induced diabetic mice model. In addition, we achieved a molecular docking study of compound 1 on PPARγ and GPR40 receptors, showing a great affinity for both targets. We observed important polar interactions between the carboxylic group and main residues into the binding pocket. Therefore, the compound 1 has a potential for the development of antidiabetic agents with newfangled dual action.
Laboratorio de Farmacología, Depto. Ciencias de la Salud, D.C.B.S., Universidad Autónoma Metropolitana- Iztapalapa, Apdo.-Postal 55-535, CP 09340, México, D.F., Mexico. Electronic address: sergio.hidalgo@ipicyt.edu.mx.
Sergio
S
Hidalgo-Figueroa
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, C.P. 62209, Cuernavaca, Morelos, Mexico.
Gabriel
G
Navarrete-Vázquez
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, C.P. 62209, Cuernavaca, Morelos, Mexico.
Samuel
S
Estrada-Soto
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, C.P. 62209, Cuernavaca, Morelos, Mexico.
Diana
D
Giles-Rivas
Laboratorio de Farmacología, Depto. Ciencias de la Salud, D.C.B.S., Universidad Autónoma Metropolitana- Iztapalapa, Apdo.-Postal 55-535, CP 09340, México, D.F., Mexico.
Francisco J
FJ
Alarcón-Aguilar
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mor. 62209, Mexico.
Ismael
I
León-Rivera
Laboratorio de Farmacología, Depto. Ciencias de la Salud, D.C.B.S., Universidad Autónoma Metropolitana- Iztapalapa, Apdo.-Postal 55-535, CP 09340, México, D.F., Mexico.
Abraham
A
Giacoman-Martínez
Laboratorio de Farmacología, Depto. Ciencias de la Salud, D.C.B.S., Universidad Autónoma Metropolitana- Iztapalapa, Apdo.-Postal 55-535, CP 09340, México, D.F., Mexico.
Elizabeth
E
Miranda Pérez
Laboratorio de Farmacología, Depto. Ciencias de la Salud, D.C.B.S., Universidad Autónoma Metropolitana- Iztapalapa, Apdo.-Postal 55-535, CP 09340, México, D.F., Mexico. Electronic address: jcap@xanum.uam.mx.
Julio C
JC
Almanza-Pérez
D016475:3T3 Cells; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004341:Drug Evaluation; D005951:Glucose Tolerance Test / Q000379:methods; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology
D001786:Blood Glucose; C517811:GPR4 protein, mouse; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D002118:Calcium; D000077205:Pioglitazone
Antidiabetic action; Dual agonist; GPR40; Insulin secretion; Molecular docking; PPARγ