A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: Design and synthesis of benzylpyrazole acylsulfonamides (original) (raw)

Design and synthesis of non-TZD peroxisome proliferator-activated receptor γ (PPARγ) modulator

Medicinal Chemistry Research, 2014

Thiazolidinediones (TZDs) are an important class of compound used for the treatment of type 2 diabetes, targeting the peroxisome proliferator-activated receptor c (PPARc). Drug-induced hepatotoxicity, edema, and weight gain are the main concerns associated with TZDs. It was unclear whether the side effects observed are target mediated or compound mediated, but most of the TZDs activate PPARc. This obliged developing of a new diverse class of ligands as antihyperglycemic agents including non-TZD PPAR ligands that could be highly effective, safe, and devoid of side effects. Here, we report the design and synthesis of N-(5-chloro-6-((1-phenylpiperidin-4-yl)oxy)pyridin-3-yl)benzenesulfonamide derivatives as non-TZD PPARc modulators.

Benzisoxazole containing Thiazolidinediones as Peroxisome Proliferator Activated Receptor-γ Agonists : Design , Molecular Docking , Synthesis & anti-diabetic studies

2014

A series of novel benzisoxazole containing thiazolidinediones were designed, docked with PPAR-γ protein leading to identification of a highly potent PPAR-γ agonist, compound S7. Based on molecular docking studies and lipinski’s rule of five, nine analogues out of 12 were synthesized and characterized by FT-IR, 1H-NMR and Mass spectra. Anti-diabetic activity of nine analogues was evaluated in alloxan (70 mg/kg, i.v.)-induced diabetes in mice [single-dose one day study]. The molecular docking and the pharmacological studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPAR-γ protein, are important for the potent activity. The acidic head part of S7 makes intensive hydrophobic interaction with the PPAR-γ protein resulting in potent activity.

Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

International Journal of Medicinal Chemistry, 2017

Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogue...

Novel Bisaryl Substituted Thiazoles and Oxazoles as Highly Potent and Selective Peroxisome Proliferator-Activated Receptor δ Agonists

Journal of Medicinal Chemistry, 2010

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor δ (PPARδ) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARδ activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARδ in skeletal muscle.

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Journal of Biological Chemistry, 2004

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPAR␣/␥ modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.

Peroxisome Proliferator-Activated Receptors as Superior Targets for Treating Diabetic Disease, Design Strategies - Review Article

Turkish Journal of Pharmaceutical Sciences

Thiazolidinedione (TZD), a class of drugs that are mainly used to control type II diabetes mellitus (T2DM), acts fundamentally as a ligand of peroxisome proliferator-activated receptors (PPARs). Besides activating pathways responsible for glycemic control via enhancing insulin sensitivity and lipid homeostasis, activating PPARs leads to exciting other pathways related to bone formation, inflammation, and cell proliferation. Unfortunately, this diverse effect via activating several pathways may show in some studies adverse health outcomes as osteological, hepatic, cardiovascular, and carcinogenic effects. Thus, an argent demand is present to find and develop new active and potent antiglycemic drugs for the treatment of T2DM. To achieve this goal, the structure of TZD for research is considered as a leading structure domain. This review would guide future research in the design of novel TZD derivatives through highlighting the general modifications conducted to the structure component of TZD scaffold affecting their potency, binding efficacy, and selectivity for the control of type II diabetes mellitus.

[4-(2H-1,2,3-Benzotriazol-2-yl)phenoxy]alkanoic Acids as Agonists of Peroxisome Proliferator-Activated Receptors (PPARs)

Chemistry & Biodiversity, 2006

A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) a, g, and d. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARa, and two of these, i.e., 1 and 5, exhibited also moderate activity on either PPARg or d with efficacy equal to 50% and 46% of that of rosiglitazone and GW 501516, respectively. Thus, compounds 1 and 5 represent interesting starting point for preparing novel agents for the treatment of dyslipidemia or of dyslipidemic type-2 diabetes.

Design and Synthesis of α-Aryloxy-α-methylhydrocinnamic Acids: A Novel Class of Dual Peroxisome Proliferator-Activated Receptor α/γ Agonists

Journal of Medicinal Chemistry, 2004

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) R/γ agonist (S)-2methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]-phenyl}-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR R/γ agonist profile (IC 50 ) 28 and 10 nM; EC50 ) 9 and 4 nM, respectively, for hPPARR and hPPARγ). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.