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Browsing by Author "Gerhard, U."
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Accelerated metabolite identification by "Extraction-NMR"
Gerhard, U.; Thomas, S.; Mortishire-Smith, R. (2003-07-14)Examples of the use of extraction-NMR, an efficient and rapid method to obtain structural information on metabolites without prior separation, are described. Crude ethyl acetate extracts of in vitro microsomal incubations ... -
Aromatic compounds from the liverwort Plagiochila spinulosa
Rycroft, D.S.; Srivastava, D.L.; Cole, W.J.; Ifeadike, P.; Kimbu, S.F.; Singh, J.; Connolly, J.D.; Thom, C.; Gerhard, U.; Organ, A.J.; Smith, R.J.; Hughes, M.; Harrison, L.J. (1999-04-10)Two known and five novel 9,10-dihydrophenanthrene derivatives, two orsellinic acid derivatives and a lunularic acid derivative have been isolated from the liverwort Plagiochila spinulosa and identified following NMR studies. ... -
Aryl sulfones : A new class of γ-secretase inhibitors
Teall, M.; Oakley, P.; Harrison, T.; Shaw, D.; Kay, E.; Elliott, J.; Gerhard, U.; Castro, J.L.; Shearman, M.; Ball, R.G.; Tsou, N.N. (2005-05-16)The development of a novel series of 4-aryl, 4-phenylsulfonyl cyclohexananone-derived γ-secretase inhibitors for the potential treatment of Alzheimer's disease is described -
Dissection of the contributions toward dimerization of glycopeptide antibiotics
Mackay, J.P.; Gerhard, U.; Beauregard, D.A.; Maplestone, R.A.; Williams, D.H. (1994-06-01)A procedure for the determination of association constants in aqueous solution using hydrogen-deuterium exchange has been developed and used to measure the dimerization constant, K(dim), for a number of strongly dimerizing ... -
The free energy change of restricting a bond rotation in the binding of peptide analogues to vancomycin group antibiotics
Gerhard, U.; Searle, M.S.; Williams, D.H. (1993-01-01)The adverse cost in free energy of restricting an internal bond rotation in the binding of the peptide ligands N-succinyl-D-alanine and N-fumaryl-D-alanine to the antibiotic Ristocetin A, has been estimated to be 3.7 ± 0.9 ... -
Glycopeptide antibiotic activity and the possible role of dimerization : A model for biological signaling
Mackay, J.P.; Gerhard, U.; Beauregard, D.A.; Westwell, M.S.; Searle, M.S.; Williams, D.H. (1994-06-01)It is demonstrated that the presence of bacterial cell wall analogues may either enhance or, in the case of ristocetin A, oppose dimerization of glycopeptide antibiotics. These observations may imply that dimerization plays ... -
H-1 NMR study of the conformation and absolute stereochemistry of two spirocyclic NK-1 antagonists
Herbert, R. H.; Gerhard, U.; Mortishire-Smith, R. J.; Thomas, S. R.; Hollingworth, G. (2005-08)The binding affinities at the human NK-1 receptor of two spirocyclic compounds were found to be similar despite being epimeric at a key stereocentre. This unexpected result prompted a thorough investigation of the solution ... -
Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma
Hop, C.E.C.A.; Wang, Y.; Kumar, S.; Elipe, M.V.S.; Raab, C.E.; Dean, D.C.; Poon, G.K.; Keohane, C.-A.; Strauss, J.; Chiu, S.-H.L.; Curtis, N.; Elliott, J.; Gerhard, U.; Locker, K.; Morrison, D.; Mortishire-Smith, R.; Thomas, S.; Watt, A.P.; Evans, D.C. (2002-01-01)[3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7 -azaspiro[4.5]decane is a substance P (Neurokinin 1 receptor) antagonist. Substance P antagonists are proven in concept to have excellent potential ... -
Identification of metabolites of a substance P (NK1 receptor) antagonist in rat hepatocytes and rat plasma
Hop, C.E.C.A.; Wang, Y.; Kumar, S.; Elipe, M.V.S.; Raab, C.E.; Dean, D.C.; Poon, G.K.; Keohane, C.-A.; Strauss, J.; Chiu, S.-H.L.; Curtis, N.; Elliott, J.; Gerhard, U.; Locker, K.; Morrison, D.; Mortishire-Smith, R.; Watt, A.P.; Evans, D.C. (2002-01-01)The metabolism of a substance P (NK1 receptor) antagonist in rat hepatocytes and rat plasma was described. The samples were prepared for analysis by protein precipitation followed by centrifugation. It was shown that the ... -
Metabolite identification in drug discovery
Watt, A.P.; Mortishire-Smith, R.J.; Gerhard, U.; Thomas, S.R. (2003-01-01)Recent developments in the technologies and approaches to identify metabolites in a drug discovery environment are reviewed. Samples may be generated using either in vitro systems - typically, but not exclusively, liver ... -
Neighboring group participation of the indole nucleus : An unusual DAST-mediated rearrangerment reaction
Hallett, D.J.; Gerhard, U.; Goodacre, S.C.; Hitzel, L.; Sparey, T.J.; Thomas, S.; Rowley, M.; Ball, R.G. (2000-08-11)A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of(3S,4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ... -
A New Pyridazine Series of GABAA α5 Ligands
Van Niel, M.B.; Wilson, K.; Adkins, C.H.; Atack, J.R.; Castro, J.L.; Clarke, D.E.; Fletcher, S.; Gerhard, U.; Mackey, M.M.; Malpas, S.; Maubach, K.; Newman, R.; O'Connor, D.; Pillai, G.V.; Simpson, P.B.; Thomas, S.R.; MacLeod, A.M. (2005-09-22)Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA α5 ... -
NK1 antagonists based on seven membered lactam scaffolds
Elliott, J. M.; Carlson, E. J.; Chcchi, G. G.; Dirat, O.; Dominguez, M.; Gerhard, U.; Jelley, R.; Jones, A. B.; Kurtz, M. M.; Tsao, K. I.; Wheeldon, A. (2006-06-01)A new class of high affinity hNK(1)R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and ... -
Partitioning of free energy contributions in the estimation of binding constants : Residual motions and consequences for amide-amide hydrogen bond strengths
Searle, M.S.; Williams, D.H.; Gerhard, U. (1992-01-01) -
Rational design and binding of modified cell-wall peptides to vancomycin-group antibiotics : Factorising free energy contributions to binding
Holroyd, S.E.; Groves, P.; Searle, M.S.; Gerhard, U.; Williams, D.H. (1993-01-01)Modified cell-wall peptides have been rationally designed and studied in a semi-quantitative approach to factorising free energy contributions in binding to vancomycin-group antibiotics in aqueous solution. Binding energies ... -
The role of the sugar and chlorine substituents in the dimerization of vancomycin antibiotics
Gerhard, U.; Mackay, J.P.; Maplestone, R.A.; Williams, D.H. (1993-01-01) -
Synthesis and conformational dynamics of tricyclic pyridones containing a fused seven-membered ring
Gibson, K.R.; Hitzel, L.; Mortishire-Smith, R.J.; Gerhard, U.; Jelley, R.A.; Reeve, A.J.; Rowley, M.; Nadin, A.; Owens, A.P. (2002-12-27)A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed ... -
Synthesis of conformationally constrained analogues of BRL32872 : Determination of stereochemistry and related pharmacological properties
Souchet, M.; Forest, M.-C.; Cheval, B.; Rouanet, S.; Faivre, J.-F.; Bril, A.; Gerhard, U.; Smith, R.J. (1997-08-05)2-Azabicyclo[2.2.2]octane derivatives have been used as conformationally constrained structure of BRL-32872, in order to investigate the effect of molecular flexibility towards class III and class IV antiarrhythmic properties. ... -
Toward an estimation of binding constants in aqueous solution : Studies of associations of vancomycin group antibiotics
Williams, D.H.; Searle, M.S.; Mackay, J.P.; Gerhard, U.; Maplestone, R.A. (1993-01-01)An approach toward the estimation of binding constants for organic molecules in aqueous solution is presented, based upon a partitioning of the free energy of binding. Consideration is given to polar and hydrophobic ... -
Toward the semiquantitave estimation of binding constants : Guides for peptide-peptide binding in aqueous solution
Williams, D.H.; Coxs, J.P.L.; Doig, A.J.; Gardner, M.; Gerhard, U.; Kaye, P.T.; Lal, A.R.; Nicholls, I.A.; Salter, C.J.; Mitchell, R.C. (1991-01-01)