Background and purpose:Ghrelin is known as a hunger hormone and plays a pivotal role in appetite, food intake, energy balance, glucose metabolism, and insulin secretion, making it a potential target for the treatment of obesity and type 2 diabetes. The essential maturation step of ghrelin to activate the GHS-R1a is the octanoylation of the Ser3, which is catalyzed by the ghrelin O-acyltransferase enzyme (GOAT) enzyme. Therefore, the inhibition of GOAT may be useful for treating ghrelin-related diseases.Experimental approach:To discover the novel inhibitors against GOAT enzyme by a fast and accurate computational method, here, we tried to develop the homology model of GOAT. Subsequently, the generated model was stabilized by molecular dynamics simulation. The consecutive process of docking, pharmacophore mapping, and large-scale virtual screening were performed to find the potential hit compounds.Findings / Results:The homology model of the GOAT enzyme was generated and the quality of 3D structures was increased to the highest level of > 99.8% of residue in allowed regions. The model was inserted into the lipid bilayer and was stabilized by molecular dynamics simulation in 200 ns. The sequential process of pharmacophore-based virtual screening led to the introduction of three compounds including ethaverine, kaempferitrin, and reglitazar as optimal candidates for GOAT inhibition.Conclusion and implications:The results of this study may provide a starting point for further investigation for drug design in the case of GOAT inhibitors and help pave the way for clinical targeting of obesity and type 2 diabetes.

01 Aug 2006·Molecular DiversityQ3 · CHEMISTRY

Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPAR γ agonists on rat primary hepatocytes and human HepG2 cells

Q3 · CHEMISTRY

Article

Author: Stacey Dial ; Levan Muskhelishvili ; Yongming Sun ; Gary Schroth ; Ernice Blann ; Yvonne P Dragan ; Lu Zhang ; Lei Guo ; Leming Shi

Agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) are a new class of oral drugs designed to treat insulin-resistant diabetes (i.e., type 2 diabetes). However, troglitazone, the first compound in the class approved by the US Food and Drug Administration (FDA) in 1997 was found to be hepatotoxic and was withdrawn from the market after reports of severe liver failure. The mechanism of PPAR gamma agonist-induced hepatotoxicity remains unknown. In this study, we examined the hepatotoxic effects of five PPAR gamma agonists (ciglitazone, pioglitazone, rosiglitazone, troglitazone, and JTT-501) on rat primary hepatocytes and human HepG2 cells. We also compared the gene expression profiles of rat primary hepatocytes after exposure to PPAR gamma agonists by using the Rat Genome Survey Microarray system from Applied Biosystems in order to understand the mechanisms of hepatotoxicities induced by PPARgamma agonists. Consistent with the hepatotoxicity data, our results demonstrate that the gene expression profiles affected by troglitazone and ciglitazone can be clearly distinguished from those by pioglitazone and rosiglitazone. Genes that are differentially expressed between the more toxic troglitazone/ciglitazone group and the less toxic rosiglitazone/pioglitazone group are involved in necrotic, apoptotic, and cell proliferative pathways. The five compounds were also clustered based on a set of molecular descriptors. The clustering based on chemical structural information is in good agreement with the clustering of compounds based on cytotoxicity or gene expression data, indicating a strong relationship between chemical structure and biological endpoints. Our work suggests that microarray analysis together with toxicological observations can be used to rank drugs for hepatotoxicity and to evaluate the safety of new compounds.

01 Feb 2005·Yao xue xue bao = Acta pharmaceutica Sinica

[Design, synthesis and insulin-sensitizing activity of some peroxisome proliferator-activated gamma agonists].

Article

Author: Zhu, Xue-jun ; Liu, Zhong-rong ; Gao, Xiao-ping ; Zhong, Chao-bin ; Wang, Xue-chao

AIMTo find new peroxisome proliferator-activated y agonists with high activity and low toxicity.METHODSBased on JTT-501 and JTT-20993, new isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds were designed and synthesized. Their insulin-sensitizing activities were evaluated.RESULTSEight new compounds were obtained. The structures of synthesized compounds were characterized by NMR, MS and IR. Four compounds (1A-4A) showed insulin-sensitizing activities.CONCLUSIONCompounds (1A and 3A) showed excellent insulin-sensitizing activities and should be worth further investigation.

100 Deals associated with Reglitazar

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KEGG	Wiki	ATC	Drug Bank
D01971	-	-	DB04971

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Phase 2	JP	Japan Tobacco, Inc.	-
Diabetes Mellitus	Phase 2	-	Pfizer Inc.	-
Diabetes Mellitus	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-
Diabetes Mellitus	Phase 1	US	Pharmacia Corp.	-

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