Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold.

We describe the parallel synthesis of novel analogs of GW0742, a peroxisome proliferator-activated receptor δ (PPARδ) agonist. For that purpose, modified reaction conditions were applied, such as a solid-phase palladium-catalyzed Suzuki coupling. In addition, tetrazole-based compounds were generated as a bioisostere for carboxylic acid-containing ligand GW0742.

Genetic and pharmacological manipulation of glyoxalase 1 regulates voluntary ethanol consumption in mice.

Previous studies have identified an association between the gene glyoxalase 1 (Glo1) and anxiety-like behavior in mice and have shown that the substrate of GLO1, methylglyoxal, is a competitive partial agonist at GABA receptors. Given the well-established role of GABA receptors in the behavioral effects of ethanol (EtOH), we investigated the role of Glo1 in voluntary EtOH consumption in mice using the drinking in the dark (DID) paradigm. Transgenic mice overexpressing Glo1 on both FVB/NJ (FVB) or C57BL/6J (B6) backgrounds showed increased voluntary EtOH consumption compared to their wild-type littermates in DID.

6-Hydroxyflavone and derivatives exhibit potent anti-inflammatory activity among mono-, di- and polyhydroxylated flavones in kidney mesangial cells.

Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4',6-dihydroxyflavone exhibited high activity with IC50 in the range of 2.

A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds.

Allosteric inhibition of coagulation enzymes offers the advantage of controlled inhibition. In this study, a small library of mono sulfated indole and benzothiazole based molecules was synthesized and screened against the panel of coagulation proteases. The results reveal that selected molecules inhibit the thrombin, factor Xa and factor XIa with moderate potency.

Anticancer activity of VDR-coregulator inhibitor PS121912.

Purpose: PS121912 has been developed as selective vitamin D receptor (VDR)-coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule.

Methods: Antiproliferation and apoptosis were determined using four different cancer cell lines (DU145, Caco2, HL-60 and SKOV3) in the presence of PS121912, 1,25-(OH)₂D₃, or a combination of 1,25-(OH)₂D₃ and PS121912.

Development of novel Vitamin D Receptor-Coactivator Inhibitors.

Nuclear receptor coregulators are master regulators of transcription and selectively interact with the vitamin D receptor (VDR) to modulate cell differentiation, cell proliferation and calcium homeostasis. Herein, we report the syntheses and evaluation of highly potent and selective VDR-coactivator inhibitors based on a recently identified 3-indolylmethanamine scaffold. The most active compound, PS121912, selectively inhibited VDR-mediated transcription among eight other nuclear receptors tested.

Glo1 inhibitors for neuropsychiatric and anti-epileptic drug development.

Many current pharmacological treatments for neuropsychiatric disorders, such as anxiety and depression, are limited by a delayed onset of therapeutic effect, adverse side effects, abuse potential or lack of efficacy in many patients. These off-target effects highlight the need to identify novel mechanisms and targets for treatment. Recently, modulation of Glo1 (glyoxalase I) activity was shown to regulate anxiety-like behaviour and seizure-susceptibility in mice.

PT19c, Another Nonhypercalcemic Vitamin D2 Derivative, Demonstrates Antitumor Efficacy in Epithelial Ovarian and Endometrial Cancer Models.

Hypercalcemia remains a major impediment to the clinical use of vitamin D in cancer treatment. Approaches to remove hypercalcemia and development of nonhypercalcemic agents can lead to the development of vitamin D-based therapies for treatment of various cancers. In this report, in vitro and in vivo anticancer efficacy, safety, and details of vitamin D receptor (VDR) interactions of PT19c, a novel nonhypercalcemic vitamin D derived anticancer agent, are described.

Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition.

We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules.

Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor.

A high-throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes for modulating gene regulation mediated by VDR. Peroxisome proliferator-activated receptor (PPAR) δ agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of > 12.

On scaffold hopping: challenges in the discovery of sulfated small molecules as mimetics of glycosaminoglycans.

The design of sulfated, small, nonsaccharide molecules as modulators of proteins is still in its infancy as standard drug discovery tools such as library of diverse sulfated molecules and in silico docking and scoring protocol have not been firmly established. Databases, such as ZINC, contain too few sulfate-containing nonsaccharide molecules, which severely limits the identification of new hits. Lack of a generally applicable protocol for scaffold hopping limits the development of sulfated small molecules as synthetic mimetics of the highly sulfated glycosaminoglycans.

Designing allosteric regulators of thrombin. Monosulfated benzofuran dimers selectively interact with Arg173 of exosite 2 to induce inhibition.

Earlier, we reported on the design of sulfated benzofuran dimers (SBDs) as allosteric inhibitors of thrombin (Sidhu et al. J. Med.

Rational design of potent, small, synthetic allosteric inhibitors of thrombin.

Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin.