Reema K. Thalji

Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase.

1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.

Benzofuran-substituted urea derivatives as novel P2Y1 receptor antagonists

Benzofuran-substituted urea analogs have been identified as novel P2Y(1) receptor antagonists. Structure-activity relationship studies around the urea and the benzofuran moieties resulted in compounds having improved potency. Several analogs were shown to inhibit ADP-mediated platelet activation.

Tetrahydro-4-quinolinamines identified as novel P2Y1 receptor antagonists

High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

Soluble epoxide hydrolase inhibition exerts beneficial anti-remodeling actions post-myocardial infarction.

BACKGROUND A contributory role for soluble epoxide hydrolase (sEH) in cardiac remodeling post-myocardial infarction (MI) has been suggested; however effects of sEH inhibition following MI have not been evaluated. In this study, we examined in vivo post-MI anti-remodeling effects of a novel sEH inhibitor (GSK2188931B) in the rat, and evaluated its direct in vitro effects on hypertrophy, fibrosis and inflammation. METHODS AND RESULTS Post-MI administered GSK2188931B (80 mg/kg/d in chow) for 5 weeks improved left ventricular (LV) ejection fraction compared to vehicle-treated (Veh) rats (P<0.01; Sham 65 ± 2%, MI+Veh 30 ± 2%, MI+GSK 43 ± 2%) without affecting systolic blood pressure. Percentage area of LV tissue sections stained positive for picrosirius red (PS) and collagen I (CI) were elevated in LV non-infarct zone (P<0.05; NIZ; PS: Sham 1.46 ± 0.13%, MI+Veh 2.14 ± 0.22%, MI+GSK 1.28 ± 0.14%; CI: Sham 2.57 ± 0.17%, MI+Veh 5.06 ± 0.58%, MI+GSK 2.97 ± 0.34%) and peri-infarct zone (P<0.001; PIZ; PS: Sham 1.46 ± 0.13%, MI+Veh 9.06 ± 0.48%, MI+GSK 6.31 ± 0.63%; CI: Sham 2.57±0.17%, MI+Veh 10.51 ± 0.64%, MI+GSK 7.77 ± 0.57%); GSK2188931B attenuated this increase (P<0.05). GSK2188931B reduced macrophage infiltration into the PIZ (P<0.05). GSK2188931B reduced AngII- and TNFα-stimulated myocyte hypertrophy, AngII- and TGFβ-stimulated cardiac fibroblast collagen synthesis, including markers of gene expression ANP, β-MHC, CTGF and CI (P<0.05). GSK2188931B reduced TNFα gene expression in lipopolysaccharide (LPS)-stimulated monocytes (P<0.05). CONCLUSION sEH inhibition exerts beneficial effects on cardiac function and ventricular remodeling post-MI, and direct effects on fibrosis and hypertrophy in cardiac cells. These findings suggest that sEH is an important contributor to the pathological remodeling following MI, and may be a useful target for therapeutic blockade in this setting.

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Significance The spread of multidrug-resistant bacteria constitutes a significant unmet medical need. Fluoroquinolone antibiotics have been compromised by resistance mutations in their targets: DNA gyrase and topoisomerase IV. Using biochemical and genetic techniques, we have identified and characterized a class of antibacterials which transforms DNA gyrase into toxic DNA-cleavage complexes, similar to fluoroquinolones, but with a distinct mechanism of action. X-ray crystallography shows that the inhibitors access a previously unexploited pocket in gyrase, leading to their activity against fluoroquinolone-resistant bacteria and providing a strategy to target bacterial topoisomerases. A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.