Publications by authors named "Royston C B Copley"

20 Publications

  • Page 1 of 1

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.

J Med Chem 2020 09 30;63(17):9093-9126. Epub 2020 Aug 30.

IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, (GSK620) and (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00796DOI Listing
September 2020

Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis.

J Med Chem 2019 10 23;62(19):8796-8808. Epub 2019 Sep 23.

GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvβ3 and αvβ5 significantly change the biological activities against αvβ6 and αvβ8. This resulted in the discovery of a pan αv antagonist (compound , 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
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http://dx.doi.org/10.1021/acs.jmedchem.9b00962DOI Listing
October 2019

Thermal and photochemical annulation of vinyl azides to 2-aminoimidazoles.

Org Biomol Chem 2019 07 24;17(27):6566-6569. Epub 2019 Jun 24.

Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Rd, PO Box 5089, Collegeville, PA 19426-0989, USA.

2-Aminoimidazoles represent useful synthons for incorporation into medicinal compounds. They provide hydrogen bonding loci, water solubilizing properties and convenient handles for further synthetic elaboration. The rapid and facile generation of diverse 2-aminoimidazoles via tandem addition cyclization reaction of vinyl azides and cyanamide has been investigated. These reactions proceeded through either thermal or photochemical activation of vinyl azides and demonstrated wide substrate scope. In the photochemical reaction, blue light (456 nm) alone triggered photolysis of the azide without the addition of a photocatalyst. Possible reaction mechanisms in the context of substrate reactivity are discussed.
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http://dx.doi.org/10.1039/c9ob01100eDOI Listing
July 2019

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

J Med Chem 2019 02 20;62(3):1180-1202. Epub 2018 Dec 20.

Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407917PMC
February 2019

Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists.

J Med Chem 2018 03 28;61(6):2518-2532. Epub 2018 Feb 28.

Neurosciences Therapeutic Area Unit , GSK Pharmaceuticals R&D , 898 Halei Road, Zhangjiang Hi-Tech Park , Pudong , Shanghai 201203 , P. R. China.

CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01854DOI Listing
March 2018

Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A.

J Org Chem 2015 Oct 30;80(19):9610-9. Epub 2015 Sep 30.

Product Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the β-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone 22. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of 1. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps.
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http://dx.doi.org/10.1021/acs.joc.5b01598DOI Listing
October 2015

Solid-state NMR analysis of a complex crystalline phase of ronacaleret hydrochloride.

J Phys Chem B 2014 Aug 18;118(34):10266-84. Epub 2014 Aug 18.

Product Development, GlaxoSmithKline plc. 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.

A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. (1)H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. (19)F and (13)C assignments for the Z' = 2 structure are obtained using DFT calculations, (19)F homonuclear dipolar correlation, and (13)C-(19)F heteronuclear dipolar correlation experiments. (35)Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract (1)H-(13)C, (1)H-(15)N, (1)H-(19)F, (13)C-(19)F, and (1)H-(35)Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase.
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http://dx.doi.org/10.1021/jp505061jDOI Listing
August 2014

Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

Org Biomol Chem 2014 Mar;12(11):1779-92

Allergy & Inflammation DPU, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

A knowledge-based library of aryl 2,3-dichlorophenylsulfonamides was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. X-ray diffraction studies were used to identify the pyrazole ring as a moiety that could bring about intramolecular hydrogen bonding with the sulfonamide NH and provide a clip or orthogonal conformation that was believed to be the preferred active conformation. Replacement of the core phenyl ring with a pyridine, and replacement of the 2,3-dichlorobenzenesulfonamide with 5-chlorothiophenesulfonamide provided compound 33 which has excellent physicochemical properties and represents a good starting point for a lead optimisation programme. Electronic structure calculations indicated that the preference for the clip or orthogonal conformation found in the small molecule crystal structures of 7 and 14 was in agreement with the order of potency in the biological assay.
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http://dx.doi.org/10.1039/c3ob42443jDOI Listing
March 2014

Solid-state NMR analysis of a boron-containing pharmaceutical hydrochloride salt.

J Pharm Sci 2013 Oct;102(10):3705-16

A novel crystalline form of the boron-containing antibacterial drug (S)-3-(aminomethyl)-7-(3-hydroxypropoxy)benzo[c] [1,2]oxaborol-1(3H)-ol hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) and single-crystal X-ray diffraction techniques. After determination of the crystal structure by X-ray diffraction, SSNMR spectroscopy of this form is performed to obtain structural information using experimental approaches based on dipolar correlation, chemical shift analysis, and quadrupolar interaction analysis. 1H SSNMR experiments at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling, 2D SSNMR experiments based on (1)H–(13)C and (1)H–(11)B dipolar heteronuclear correlation, and density functional theory (DFT) calculations are combined in a novel approach to obtain a nearly complete assignment of the (1)H spectrum of this crystalline phase. (11)B and (35)Cl chemical shift and quadrupolar parameters are obtained using the analysis of MAS spectra and are found to be accurately reproduced using DFT calculations. NMR chemical shielding and electric field gradient parameters obtained using these methods are related to hydrogen-bonding trends in the crystal structure. The results illustrate the increasing capability of SSNMR techniques involving (1)H, (11)B, and (35)Cl SSNMR in the analysis of the crystal structure of a pharmaceutical compound containing covalently bonded boron.
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http://dx.doi.org/10.1002/jps.23679DOI Listing
October 2013

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

J Med Chem 2013 Mar 27;56(5):1946-60. Epub 2013 Feb 27.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
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http://dx.doi.org/10.1021/jm301572hDOI Listing
March 2013

One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability.

J Pharm Sci 2011 Oct 16;100(10):4302-16. Epub 2011 May 16.

Product Development, GlaxoSmithKline plc., King of Prussia, Pennsylvania 19406.

Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin-derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline-amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability.
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http://dx.doi.org/10.1002/jps.22621DOI Listing
October 2011

Studying the origin of the antiferromagnetic to spin-canting transition in the beta-p-NCC6F4CNSSN* molecular magnet.

Chemistry 2010 Mar;16(9):2741-50

Departament de Química Física & IQTCUB, Universitat de Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain.

The crystal structure of the spin-canted antiferromagnet beta-p-NCC(6)F(4)CNSSN* at 12 K (reported in this work) was found to adopt the same orthorhombic space group as that previously determined at 160 K. The change in the magnetic properties of these two crystal structures has been rigorously studied by applying a first-principles bottom-up procedure above and below the magnetic transition temperature (36 K). Calculations of the magnetic exchange pathways on the 160 K structure reveal only one significant exchange coupling (J(d1)=-33.8 cm(-1)), which generates a three-dimensional diamond-like magnetic topology within the crystal. The computed magnetic susceptibility, chi(T), which was determined by using this magnetic topology, quantitatively reproduces the experimental features observed above 36 K. Owing to the anisotropic contraction of the crystal lattice, both the geometry of the intermolecular contacts at 12 K and the microscopic J(AB) radical-radical magnetic interactions change: the J(d1) radical-radical interaction becomes even more antiferromagnetic (-43.2 cm(-1)) and two additional ferromagnetic interactions appear (+7.6 and +7.3 cm(-1)). Consequently, the magnetic topologies of the 12 and 160 K structures differ: the 12 K magnetic topology exhibits two ferromagnetic sublattices that are antiferromagnetically coupled. The chi(T) curve, computed below 36 K at the limit of zero magnetic field by using the 12 K magnetic topology, reproduces the shape of the residual magnetic susceptibility (having subtracted the contribution to the magnetization arising from spin canting). The evolution of these two ferromagnetic J(AB) contributions explains the change in the slope of the residual magnetic susceptibility in the low-temperature region.
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http://dx.doi.org/10.1002/chem.200903221DOI Listing
March 2010

Elucidating the pathways of degradation of denagliptin.

J Pharm Sci 2010 Jul;99(7):3030-40

Analytical Sciences, Chemical Development, Five Moore Drive, PO Box 13398, GlaxoSmithKline, RTP, North Carolina 27709, USA.

Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway.
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http://dx.doi.org/10.1002/jps.22069DOI Listing
July 2010

An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium ions: a facile synthesis of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones.

Org Biomol Chem 2009 Sep 9;7(17):3561-71. Epub 2009 Jul 9.

Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK.

The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.
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http://dx.doi.org/10.1039/b907400gDOI Listing
September 2009

Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase.

J Org Chem 2008 Apr 22;73(8):3094-102. Epub 2008 Mar 22.

Chemical Development, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.
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http://dx.doi.org/10.1021/jo800062cDOI Listing
April 2008

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: crystal structures and multinuclear solid-state NMR.

J Pharm Sci 2008 Nov;97(11):4756-82

Preclinical Development, GlaxoSmithKline plc., 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA.

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.
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http://dx.doi.org/10.1002/jps.21336DOI Listing
November 2008

An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT-2331 using vibrational circular dichroism.

Chirality 2007 Sep;19(9):731-40

GlaxoSmithKline, Discovery Research, Research Triangle Park, NC 27709, USA.

GT-2331 [(+)-1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the histamine H3 receptor, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X-ray diffraction studies have provided conflicting data, leaving its three-dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)-enantiomer.
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http://dx.doi.org/10.1002/chir.20431DOI Listing
September 2007

Exo-pi-bonding to an ortho-carborane hypercarbon atom: systematic icosahedral cage distortions reflected in the structures of the fluoro-, hydroxy- and amino-carboranes, 1-X-2-Ph-1,2-C2B10H10 (X=F, OH or NH2) and related anions.

Dalton Trans 2004 Sep 4(17):2786-99. Epub 2004 Aug 4.

Chemistry Department, Durham University Science Laboratories, South Road, Durham, UK.

The structures of derivatives of phenyl-ortho-carborane bearing on the second cage hypercarbon atom a pi-donor substituent (F, OH, O-, NH2, NH- and CH2-) were investigated by NMR, X-ray crystallography and computational studies. The molecular structures of these compounds, notably their cage C1-C2 distances and the orientations of their pi-donor substituents (OH, NH2, NH- and CH2-) show remarkable and systematic variations with the degree of exo pi-bonding, which varies as expected with the pi-donor characteristics of the substituent.
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http://dx.doi.org/10.1039/B406422DDOI Listing
September 2004

Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.

Bioorg Med Chem Lett 2004 Aug;14(15):3937-41

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
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http://dx.doi.org/10.1016/j.bmcl.2004.05.070DOI Listing
August 2004

Absolute stereochemistry of ibhayinol from a South African sea hare.

J Nat Prod 2002 Apr;65(4):580-2

Department of Chemistry, Rhodes University, Grahamstown, South Africa.

The absolute stereochemistry of the tricyclic, sesquiterpene ibhayinol (5) extracted from the sea hare Aplysia dactylomela, collected in Algoa Bay, South Africa, was established as 1S, 3S, 4S, 6R, 7S, 10R, 11S from a single-crystal X-ray diffraction experiment. The structure of ibhayinol suggested that 8-dehydroxy-1-deacetylalgoane (7) might be a biosynthetic precursor of this compound.
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http://dx.doi.org/10.1021/np010403sDOI Listing
April 2002