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

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.

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists.

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp/sp character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro.

Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode.

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF to the pyrrolidine improves the human GPR40 binding K and agonist efficacy.

Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice.

Background: Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined.

Methodology And Principal Findings: We initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species.

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats.

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029).

Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance.

Objective: Insulin resistance develops in tandem with obesity. Ablating myostatin (Mstn) prevents obesity, so we investigated if Mstn deficiency could improve insulin sensitivity. A loss-of-function mutation (Mstn(Ln)) in either one or both alleles of the Mstn gene shows how Mstn deficiency protects whole-body insulin sensitivity.

Acetaminophen overdose in pregnancy.

Acetaminophen (APAP) is the most common drug overdose in pregnancy. Available data regarding APAP overdose in pregnancy is limited to case reports and a small prospective case series. APAP has been demonstrated to cross the placenta and in toxic doses may harm the fetal and maternal hepatocytes.

Topiramate treatment causes skeletal muscle insulin sensitization and increased Acrp30 secretion in high-fat-fed male Wistar rats.

We show that Topiramate (TPM) treatment normalizes whole body insulin sensitivity in high-fat diet (HFD)-fed male Wistar rats. Thus drug treatment markedly lowered glucose and insulin levels during glucose tolerance tests and caused increased insulin sensitization in adipose and muscle tissues as assessed by euglycemic clamp studies. The insulin-stimulated glucose disposal rate increased twofold (indicating enhanced muscle insulin sensitivity), and suppression of circulating FFAs increased by 200 to 300%, consistent with increased adipose tissue insulin sensitivity.

Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats.

We have studied the in vivo and in vitro effects of Topiramate (TPM) in female Zucker diabetic fatty (ZDF) rats. After weight matching, drug treatment had a marked effect to lower fasting glucose levels of relatively normoglycemic animals as well as during an oral glucose tolerance test. The glucose clamp studies revealed a approximately 30% increased glucose disposal, increased hepatic glucose output (HGO) suppression from approximately 30 to 60%, and an increased free fatty acid suppression from 40 to 75%.

Muscle-specific Pparg deletion causes insulin resistance.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle.

Chronic endothelin-1 treatment leads to insulin resistance in vivo.

We determined whether chronic endothelin-1 (ET-1) treatment could lead to in vivo insulin resistance. Like insulin, ET-1 acutely stimulated glucose transport in isolated soleus muscle strips of WKY rats. ET-1 pretreatment (1 h) decreased insulin-stimulated glucose transport in muscle strips (-23%).