Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A).

A number of pyrazolopyrimidines were synthesized and tested for their positive allosteric modulation of the HCA(2) receptor (GPR109A). Compound 24, an efficacious and potent agonist and allosteric enhancer of nicotinic acid's action, was the basis for most other compounds. Interestingly, some of the compounds were found to increase the efficacy of the endogenous ligand 3-hydroxybutyrate and enhance its potency almost 10-fold. This suggests that the pyrazolopyrimidines may have therapeutic value when given alone.

Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor.

The luteinizing hormone (LH) receptor plays an important role in fertility and certain cancers. The endogenous ligands human chorionic gonadotropin (hCG) and LH bind to the large N terminal domain of the receptor. We recently reported on the first radiolabeled low molecular weight (LMW) agonist for this receptor, [(3)H]Org 43553, which was now used to screen for new LMW ligands. We identified a terphenyl derivative that inhibited [(3)H]Org 43553 binding to the receptor, which led us to synthesize a number of derivatives. The most potent compound of this terphenyl series, 24 (LUF5771), was able to increase the dissociation rate of [(3)H]Org 43553 by 3.3-fold (at 10 muM). In a functional assay, the presence of 24 resulted in a 2- to 3-fold lower potency of both Org 43553 and LH. Thus, the compounds presented in this paper are the first LMW ligands that allosterically inhibit the LH receptor.

Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography.

BACKGROUND: Recent studies indicate that MRI, after administration of gadolinium-diethylenetriamine pentaacetic acid, can identify nonviable areas in dysfunctional myocardium. We compared MRI hyperenhancement with PET as a gold standard for detection and quantification of myocardial scar tissue. METHODS AND RESULTS: Thirty-one patients with ischemic heart failure (ejection fraction, 28+/-9%) were imaged with PET and MRI. Scar was defined as regionally increased MRI signal intensity 20 minutes after injection of 0.2 mmol/kg gadolinium-diethylenetriamine pentaacetic acid and as concordantly reduced perfusion and glucose metabolism as defined by PET. Sensitivity and specificity of MRI in identifying patients and segments (n=1023) with matched flow/metabolism defects was 0.96 of 1.0 and 0.86 of 0.94, respectively. Eleven percent of segments defined as viable by PET showed some degree of MRI hyperenhancement. Defect severity score based on visual analysis was 44.3+/-9.1 for PET and 47.6+/-11.1 for MRI (r=0.91, P<0.0001). Quantitatively assessed relative MRI infarct mass correlated well with PET infarct size (r=0.81, P<0.0001). Furthermore, MRI hyperenhancement was a better predictor of scar tissue than end-diastolic and end-systolic wall thickness or thickening. CONCLUSIONS: In severe ischemic heart failure, MRI hyperenhancement as a marker of myocardial scar closely agrees with PET data. Although hyperenhancement correlated with areas of decreased flow and metabolism, it seems to identify scar tissue more frequently than PET, reflecting the higher spatial resolution. Additional functional studies after revascularization are required to define the significance of small islands of scar detected by MRI.