Design and synthesis of potent and subtype-selective PPARα agonists (original) (raw)
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Design and synthesis of potent and subtype-selective PPARa agonists
Bioorg Medicinal Chem Letter, 2006
Beginning with a moderately potent PPARc agonist 9, a series of potent and highly subtype-selective PPARa agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.
Design and synthesis of a novel class of dual PPARγ/δ agonists
Bioorganic & Medicinal Chemistry Letters, 2007
The design and synthesis of dual PPAR c/d agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phen-yl}propionic acid is described. This compound dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats and produced less weight gain relative to rosiglitazone at an equivalent level of glucose control.
Minireview: Challenges and Opportunities in Development of PPAR Agonists
Molecular Endocrinology
The clinical impact of the fibrate and thiazolidinedione (TZD) drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, PPAR-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here, we review concepts employed to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and non-genomic regulation. We briefly describe the recently discovered non-PPAR protein targets of TZDs, mitoNEET and mTOT. Finally, we summarize the contributions...
European Journal of Pharmacology, 2008
Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARα and γ with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-{2[4-(4chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy}-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARα and γ without activating PPARδ. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (α and γ; 2.84 μM and 3.02 μM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulinresistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED 30 = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL-(ED 30 = 0.13 mg/kg) and total cholesterol (ED 30 = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARα and PPARγ in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARα/γ dual agonists.
Bioorganic & Medicinal Chemistry Letters, 2005
Herein we describe a series of potent and selective PPARc agonists with moderate PPARa affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
Structure–activity relationships of dimeric PPAR agonists
Bioorganic & Medicinal Chemistry Letters, 2005
A series of dimeric PPAR agonists were designed and tested for PPAR activity in vitro. The SAR showed that dimeric ligands with a common group or full dimeric ligands had retained or even increased PPARc potency. The dimeric agonist concept can be used to fine tune the subtype selectivity of PPAR agonists. The PPARc potency could, at least partly, be explained using molecular modeling.
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...