No abstract

The room-temperature synthesis of meso-porphyrins has been investigated at aldehyde and pyrrole concentrations >0.1 M using tetraphenylporphyrin (TPP) and tetramesitylporphyrin (TMP) as models. The decline in yield that occurs at higher reactant concentrations can be offset partially with higher acid catalyst concentrations. Reactions of 0.1 M benzaldehyde and pyrrole afford 20-30% yields of TPP at appropriate concentration of three acids, trifluoroacetic acid, BF3*OEt2, or methanesulfonic acid, using the two-step process of acid-catalyzed condensation followed by quinone oxidation. A one-step synthesis of porphyrins has been investigated where aldehyde, pyrrole, acid catalyst, and oxidant are present simultaneously. Among five quiñones examined only p-chloranil (TCQ) provides successful oxidation. The one-step synthesis performed at concentrations of 0.1 M affords TPP in 10-20 % yields. Both the one-and two-step syntheses at high concentrations involve slurries due to the amount of TCQ required for oxidation. An electron transport chain employing TCQ and iron(II) phthalocyanine (FePc) in catalytic amounts and O2 as the terminal electron acceptor has been adapted for the porphyrin synthesis. FePc activates O2 and recycles reduced TCQ at room temperature. This electron transport chain provides mild aerobic oxidation. The aerobic oxidation process is cleaner than oxidation with stoichiometric amounts of TCQ and can be implemented as part of a one-step or two-step porphyrin synthesis. Reaction of 0.1 M benzaldehyde and pyrrole with acid catalysis in the presence of 5 mol % TCQ and 5 mol % FePc with gentle aeration affords TPP in 11% (one step) or 24% (two step) yield. Mesitaldehyde is converted to tetramesitylporphyrin upon reaction at a concentration of 0.1 M with BF3-ethanol cocatalysis and aerobic oxidation. The two-step synthesis with aerobic oxidation proceeds under mild ambient conditions, affords ~100 mg porphyrin from 50-mL reactions, and should prove generally useful for preparative scale syntheses of meso-porphyrins.

Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.

A novel nonthiazolidinedione dual peroxisome proliferator-activated receptor (PPAR)-␣/␥ 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 ⅐ kg -1 ⅐ 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-␥ agonist, which were presumably due to the concomitant PPAR-␣ 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 cardiovacular 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.

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.