Pryde D.C.,Pfizer |
Jones L.H.,Pfizer |
Gervais D.P.,Pfizer |
Gervais D.P.,Public Health England |
And 20 more authors.
PLoS ONE | Year: 2013
Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences. © 2013 Pryde et al.
Blumberg L.C.,Alkermes |
Zeidan T.A.,Alkermes |
Maddaford A.,Peakdale Molecular Ltd |
Warren N.C.,Peakdale Molecular Ltd |
Hutchison P.,Peakdale Molecular Ltd
RSC Advances | Year: 2013
An unexpected regioisomer was observed during the synthesis of olanzapine prodrugs. N-5-(acyloxyalkoxy)carbonyl-functionalized olanzapine derivatives were found to have favorable physicochemical properties, such as crystallinity, melting points, solubility and plasma conversion profiles suitable for formulation as extended-release injections. © The Royal Society of Chemistry 2013.
Chapron C.,Idenix Pharmaceuticals |
Glen R.,Peakdale Molecular Ltd. |
La Colla M.,Idenix Pharmaceuticals |
Mayes B.A.,Idenix Pharmaceuticals |
And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014
The synthesis of 2′-O,4′-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2′-C-methyl or 5′-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2′-C-methyl- and 5′-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2′-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay. © 2014 Elsevier Ltd. All rights reserved.
Qin P.,Ecole Polytechnique Federale de Lausanne |
Tetreault N.,Ecole Polytechnique Federale de Lausanne |
Dar M.I.,Ecole Polytechnique Federale de Lausanne |
Gao P.,Ecole Polytechnique Federale de Lausanne |
And 11 more authors.
Advanced Energy Materials | Year: 2015
(Figure Presented) A polytriarylamine-based oligomer is reported as a hole transporting material and its application in solid-state CH3NH3PbI3 based heterojunction solar cells is described. It yields a power conversion efficiency of 12.0% under 99.6 mW cm-2 illumination. In addition to suitable energy levels and high hole mobility, the low preparation cost makes it a promising candidate for photovoltaics. © 2014 Wiley-VCH Verlag GmbH & Co. KYWGaA.
Wainwright P.,Peakdale Molecular Ltd. |
Maddaford A.,Peakdale Molecular Ltd. |
Simms M.,Peakdale Molecular Ltd. |
Forrest N.,Peakdale Molecular Ltd. |
And 8 more authors.
Synlett | Year: 2011
A novel systematic approach to the synthesis of 2-cyano-7-deaza-8-azapurine derived nucleosides is described. It is shown how this chemistry was developed with the labile 2-substituted nitrile position in mind, and also how the same approach is applicable to 2-cyano-8-azapurine derived nucleosides. © 2011 Georg Thieme Verlag Stuttgart New York.
Pryde D.C.,Pfizer |
Middleton D.S.,Pfizer |
Stephenson P.T.,Pfizer |
Wainwright P.,Peakdale Molecular Ltd |
And 7 more authors.
Tetrahedron Letters | Year: 2011
Robust practical routes to three different carbon-substituted nucleosides are described. Short synthetic procedures for preparing 1-homonucleosides, 2'-C-methyl-carbanucleosides and 2'-C-methyl-cyclopro-pyl/cyclopentyl fused bicyclic ribose analogues are described starting from readily available building blocks. Crown Copyright © 2011 Published by Elsevier Ltd. All rights reserved.
Wishka D.G.,Pfizer |
Beagley P.,Peakdale Molecular Ltd. |
Lyon J.,Peakdale Molecular Ltd. |
Farley K.A.,Pfizer |
Synthesis | Year: 2011
Bridged bicyclic morpholines are important building blocks in medicinal chemistry research. The bicyclic morpholine 6-oxa-3-azabicyclo[3.1.1]heptane (2a) is of particular interest as a morpholine isostere because it is achiral and shows properties similar to that of morpholine based on a derived analogue. The first synthesis of morpholine 2a (tosylate salt) is described. The six-step sequence begins with inexpensive starting materials and uses straightforward chemistry. © Georg Thieme Verlag Stuttgart. New York.
Pryde D.C.,Pfizer |
Webster R.,Pfizer |
Butler S.L.,Pfizer |
Murray E.J.,Pfizer |
And 15 more authors.
MedChemComm | Year: 2013
In the present article, we describe SAR studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors that led to a candidate compound, PF-4776548, of high potency and with an excellent resistance profile. Uncertainties around the human pharmacokinetic predictions for PF-4776548 led to the compound being taken into a human microdose study to confirm its human pharmacokinetics, the results of which are described herein. © 2013 The Royal Society of Chemistry.
Mccall K.L.,Center for Process Innovation |
Rutter S.R.,Center for Process Innovation |
Bone E.L.,Center for Process Innovation |
Forrest N.D.,Peakdale Molecular Ltd. |
And 7 more authors.
Advanced Functional Materials | Year: 2014
High mobility organic semiconductor formulations with excellent uniformity across large area substrates are prepared via the use of formulations containing small molecule and high permittivity semiconducting oligomers. The use of these high-k (k > 3.3) oligomers allows control of the wetting via the manipulation of the surface energy of the substrate being coated. Organic thin film transistors results with mobilities of up to 5 cm2 V -1 s-1, standard deviation <10 %, on/off ratios of 109 are presented. High mobility organic semiconductor formulations with excellent uniformity are prepared by combining a small molecule and high permittivity semiconducting oligomers. The use of these high-k (k > 3.3) oligomers allows control of the performance by manipulation of the surface energy of the substrate. Organic thin film transistors results with mobilities of 5 cm2 V-1 s-1, standard deviation <10% and on/off ratios of 109 are presented. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Peakdale Molecular Ltd and Center for Process Innovation Ltd | Date: 2012-05-24
This invention comprises a semiconducting polymer having a permittivity greater than 3.4 at 1000 Hz and a charge mobility in the pure state greater than 10^(7 )cm^(2)V^(1)s^(1 )and more preferably greater than 10^(6 )cm^(2)V^(1)s^(1). Preferred polymers include repeating units of triarylamines which have specific cyano and/or alkoxy substitution. They are suitable for use in electronic components such as organic thin film transistors.