Indanylacetic acids as PPAR-δ activator insulin sensitizers (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2007
Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.
Indian Journal of Pharmaceutical Education and Research, 2019
Aim: The increasing incidences of type 2 diabetes mellitus, represents a considerable public health problem and characterized by loss in sensitivity of tissues to insulin which can be restored by activation of Peroxisome Proliferator-Activated Receptors (PPARs). The present work takes in consideration for the development of PPAR agonists, which can activate PPARs and is expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol and normalize hyperglycaemia. Materials and Methods: Quantitative Structure-Activity Relationship (QSAR) study is performed by means of Multiple Linear Regression (MLR) analysis on a set of indanyl acetic acid derivatives followed by ADMET prediction and Docking Studies. Results: A good correlation is found by regression analysis between the observed and predicted activities as evident by their R 2 (0.81), Q 2 (0.81) and R 2 pred (0.86) for PPARα and R 2 (0.66), Q 2 (0.66) and R 2 pred (0.90) for PPARδ and R 2 (0.82), Q 2 (0.77) and R 2 pred (0.58) for PPARγ respectively. Molecular docking of the ligands qualifying all the Drug Likeness properties to the proteins PPARα (PDB ID: 3ET1), PPARδ (PDB ID: 3ET2) and PPARγ (PDB ID: 3ET3) with FlexX score-11.98,-9.69 and-21.48 respectively followed by core hoping. Conclusion: Docking studies revealed that hydrogen-bonding interactions are crucial for the binding of ligands with the target. Core replacement of the best-docked conformations of the selected ligand is performed in order to obtain more potent and novel ligands.
Design and synthesis of indane-ureido-thioisobutyric acids: A novel class of PPARα agonists
Bioorganic & Medicinal Chemistry Letters, 2007
A series of aminoindane derivatives were synthesized and shown to be potent PPARa agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARa activation and PPARa mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.
Journal of Medicinal Chemistry, 2007
Aim: The increasing incidences of type 2 diabetes mellitus, represents a considerable public health problem and characterized by loss in sensitivity of tissues to insulin which can be restored by activation of Peroxisome Proliferator-Activated Receptors (PPARs). The present work takes in consideration for the development of PPAR agonists, which can activate PPARs and is expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol and normalize hyperglycaemia. Materials and Methods: Quantitative Structure-Activity Relationship (QSAR) study is performed by means of Multiple Linear Regression (MLR) analysis on a set of indanyl acetic acid derivatives followed by ADMET prediction and Docking Studies. Results: A good correlation is found by regression analysis between the observed and predicted activities as evident by their R 2 (0.81), Q 2 (0.81) and R 2 pred (0.86) for PPARα and R 2 (0.66), Q 2 (0.66) and R 2 pred (0.90) for PPARδ and R 2 (0.82), Q 2 (0.77) and R 2 pred (0.58) for PPARγ respectively. Molecular docking of the ligands qualifying all the Drug Likeness properties to the proteins PPARα (PDB ID: 3ET1), PPARδ (PDB ID: 3ET2) and PPARγ (PDB ID: 3ET3) with FlexX score-11.98,-9.69 and-21.48 respectively followed by core hoping. Conclusion: Docking studies revealed that hydrogen-bonding interactions are crucial for the binding of ligands with the target. Core replacement of the best-docked conformations of the selected ligand is performed in order to obtain more potent and novel ligands.
A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity
2001
esting is the observation that the antidiabetic activity of and Johan Auwerx 1,4 a group of synthetic compounds, i.e., the glitazones, 1 Institut de Gé né tique et de Biologie Molé culaire which possess a thiazolidinedione ring, results from et Cellulaire their PPAR␥-activating properties (Berger et al., 1996; CNRS/INSERM/ULP Willson et al., 1996). The therapeutic efficacy of the cur-67404 Illkirch rent thiazolidinediones in type 2 diabetes is, however, France far from optimal, and several side effects have been 2 INSERM reported (Schoonjans and Auwerx, 2000), which ex-CHRU plains the intensive search for nonthiazolidinedione 59037 Lille PPAR␥ ligands. France Recently, a series of L-Tyr-based PPAR␥ ligands was 3 Departments of Molecular Biochemistry designed by replacing the thiazolidinedione ring with a and Endocrinology carboxylic acid and by introducing an amine function GlaxoWellcome Research and Development on the adjacent carbon while keeping the parahydroxy-Research Triangle Park, North Carolina 27709 benzyl sequence (Figure 1A). An optimal PPAR␥ activity was obtained when the amine on the ␣ carbon of the L-Tyr ligands was substituted with a benzoylphenyl Summary function, leading to the development of N-(2-benzoylphenyl)-L-Tyr derivatives (Henke et al., 1998). Rigidify-FMOC-L-Leucine (F-L-Leu) is a chemically distinct ing the benzoyl and phenyl moieties of this ␣ amino PPAR␥ ligand. Two molecules of F-L-Leu bind to the substituent through an additional phenyl-phenyl bond ligand binding domain of a single PPAR␥ molecule, (Figure 1A) leads to compounds with good potencies.
World Journal of Pharmaceutical Research
Aims: To explains novel targets of currently used and new insulin sensitizers with emphasis on Sodium-glucose cotransporter-2 (SGLT- 2) inhibitors, G-protein-coupled receptors (GPCRs), thiazolidinediones, insulin secretogogues, and stem cell therapy. Method: Review of recent literature that emphasizes on novel targets and techniques belonging to glucose-lowering drugs and therapeutic intervention especially those studies that focus on new insulin sensitizers. Results and conclusion: Diabetes is a global major health problem that needs challenging and renewable medications every day as we need to individualize both treatment targets and treatment strategies. Identification of novel targets and techniques for therapeutic intervention will lead to more personalized approaches to treatment and hence to define which medication to be used in whom with regard to benefits and side effects.
2013
Diabetes mellitus (DM) is a progressive disease cha racterized by hyperglycemia due to insulin deficien cy and insulin resistance or both. The fasting and postpra ndial blood glucose gets elevated, exposing the pat ient to acute and chronic complications (micro- and macro-vascular) leads to blindness, kidney failure, heart diseas e, stroke and amputations. Diabetes mellitus is one of the most c ommon endocrine disorders affecting almost 6% of the world's population. The number of diabetic patients will re ach 300 million in 2025. More than 97% of these pat ients will have type II diabetes. "Glitazones," bind to ppar-γ, a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. These PPAR-γ acts on Peroxisome Proliferator Responsive Element s (PPRE). In the present article, Rhodanine analogs w ere screened for their anti diabetic activity. Rosi glitazone is used as a reference standard. The compounds R2, R5 and R7 sho...