- Full text PDF available (3)
- This year (1)
- Last 5 years (5)
- Last 10 years (12)
Journals and Conferences
Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a… (More)
A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination… (More)
A novel synthetic strategy is described which may be used to prepare analogues of the antimalarial, fungal metabolite apicidin. Compared to the natural product, one analogue shows potent and selective activity in vitro against the parasite Trypanosoma brucei and low mammalian cell toxicity.
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
The enantioselective addition of organolithium reagents to N-anisyl aldimines promoted by chiral bisoxazolines and (-)-sparteine as external ligands is described. This reaction proceeds readily with a wide range of aldimine substrates (aliphatic, aromatic, olefinic) and organolithium nucleophiles (Me, n-Bu, Ph, vinyl) in excellent yields (81-99%) and with… (More)
A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current… (More)
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha… (More)
The 2014 CSAR Benchmark Exercise was the last community-wide exercise that was conducted by the group at the University of Michigan, Ann Arbor. For this event, GlaxoSmithKline (GSK) donated unpublished crystal structures and affinity data from in-house projects. Three targets were used: tRNA (m1G37) methyltransferase (TrmD), Spleen Tyrosine Kinase (SYK),… (More)
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies… (More)
Of all the in vitro mutagenicity assays, the Ames test displays the best correlation with rodent carcinogenicity and therefore carries significant weight with the food and drug regulatory bodies. Aromatic amines (AA) are ubiquitous structural groups in food and drug molecules despite the well-documented mutagenic and carcinogenic propensity for many… (More)