ABSTRACT
A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
Subject(s)
Amides/chemistry , Drug Design , Indoles/chemical synthesis , PPAR delta/agonists , PPAR gamma/agonists , Animals , Combinatorial Chemistry Techniques , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , RatsABSTRACT
The design and synthesis of dual PPAR gamma/delta agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}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.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , PPAR delta/agonists , PPAR gamma/agonists , Animals , Blood Glucose/metabolism , Dose-Response Relationship, Drug , Drug Design , Female , Half-Life , Humans , Hypoglycemic Agents/pharmacokinetics , Indicators and Reagents , Insulin/blood , Male , Rats , Rats, Sprague-Dawley , Rats, Zucker , Rosiglitazone , Structure-Activity Relationship , Thiazolidinediones/pharmacology , Weight Gain/drug effectsABSTRACT
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
Subject(s)
Hypoglycemic Agents/chemical synthesis , PPAR delta/agonists , PPAR gamma/agonists , Phenyl Ethers/chemical synthesis , Phenylpropionates/chemical synthesis , Weight Gain/drug effects , Animals , Blood Glucose/metabolism , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Dyslipidemias/drug therapy , Female , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Male , Mice , PPAR alpha/genetics , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Radioligand Assay , Stereoisomerism , Transcriptional ActivationABSTRACT
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.
Subject(s)
Cinnamates/chemical synthesis , Models, Molecular , PPAR alpha/agonists , Animals , Cinnamates/chemistry , Cinnamates/pharmacology , Drug Design , Humans , Ligands , Mice , Molecular Structure , Species Specificity , Structure-Activity RelationshipABSTRACT
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-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 alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemical synthesis , Transcription Factors/agonists , Animals , Binding, Competitive , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Radioligand Assay , Rats , Rats, Zucker , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.
Subject(s)
Anticholesteremic Agents/pharmacology , Gluconeogenesis/drug effects , Hypoglycemic Agents/pharmacology , Liver/drug effects , Receptors, Cytoplasmic and Nuclear/agonists , Animals , DNA-Binding Proteins , Dose-Response Relationship, Drug , Female , Hydrocarbons, Fluorinated , Liver/metabolism , Liver X Receptors , Male , Mice , Orphan Nuclear Receptors , Rats , Rats, Zucker , SulfonamidesABSTRACT
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.