Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the ...identification of non-carboxylate inhibitors derived from pyrido3,4-dpyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic ...acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6–8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100–125 nM).
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood ...activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
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The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood ...activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
HIV-1 is a master at deceiving the immune system and usurping host biosynthetic machinery. Although HIV-1 is coated with host-derived glycoproteins, only glycosylation of viral gp120 has been ...described. Here we use lectin microarray technology to analyze the glycome of intact HIV-1 virions. We show that the glycan coat of human T cell line-derived HIV-1 matches that of native immunomodulatory microvesicles. The carbohydrate composition of both virus and microvesicles is cell-line dependent, which suggests a mechanism to rapidly camouflage the virus within the host. In addition, binding of both virus and microvesicles to antiviral lectins is enriched over the host cell, raising concern about targeting these glycans for therapeutics. This work also sheds light on the binding of HIV-1 to galectin-1, an important human immune lectin. Overall, our work strongly supports the theory that HIV-1 co-opts the exocytic pathway of microvesicles, thus potentially explaining why eliciting a protective antiviral immune response is difficult.
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the ...first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
A series of quinoline-3-carboxamides has been identified as potent inhibitors of PDE4. The SAR has been explored and these studies have highlighted compounds
43 and
48 which show good potency, ...selectivity and rat PK suitable for oral dosing. The crystal structure of an example quinoline bound into the active site of PDE4 is also described.
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
Global fits combining existing rotational spectroscopy data for both chlorine isotopologues of AlCl and BiCl provide 2x/8x improved precision in hyperfine parameters like the nuclear electric ...quadrupole moment coupling terms (eQq) for use in novel physics applications, and include Born–Oppenheimer Breakdown (BOB) terms. The BiF fit combines existing data for a range of rotational transitions, providing an almost 3x more precise eQq benchmark for theoretical work on related molecules used in searches for the electric dipole moment of the electron (eEDM). Our AlCl nuclear electric quadrupole moment ratio Q(35Cl):Q(37Cl) of 1.26858(37) confirms many previous values, while enabling a more precise BiCl eQq value and informing reference work choices for nuclear physics Q-values for both Cl isotopes.
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•Global AlCl fit gives BOB & 2x better hyperfine data for laser cooling & astrophysics.•Global BiCl/BiF fits yield 8x better Cl & 8x/3x better benchmark Bi eQq values.•Use spectroscopic Cl eQq ratios in choosing nuclear physics reference Q-values (!).
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