Chemical science

Pearl River, NY, United States

Chemical science

Pearl River, NY, United States
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PubMed | Glaxosmithkline and Chemical science
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

2,5-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2,5-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity.


Ginosar D.M.,Chemical science | Petkovic L.M.,Chemical science | Rollins H.W.,Chemical science | Burch K.C.,Chemical science | Schaefers B.,BKS Energy LLC
10AIChE - 2010 AIChE Annual Meeting, Conference Proceedings | Year: 2010

BKS Energy and the Idaho National Laboratory have developed a unique synthesis method to produce alkali metal promoted catalysts for the conversion of synthesis gas to mixed alcohols. Experimental results have shown that the catalysts can produce high reaction rates with significant conversion to higher alcohols including ethanol, propanols and butanols while keeping selectivity to hydrocarbons low. Production rates are on the order of 1,000 g product per kilogram catalyst per hour with selectivity to hydrocarbons of approximately 6 wt%. Selectivity to methanol is still relatively high (43 wt%); however, selectivity to higher alcohols are 50 wt%. Of the higher alcohols, butanols represent 54 wt%, propanols 28 wt%, and ethanol 18 wt%. This paper will present the effect of process conditions on catalyst activity and selectivity as well as the effect of CO2 concentrations in the feed on yield and selectivity.


Bernotas R.C.,Collegeville | Singhaus R.R.,Collegeville | Kaufman D.H.,Collegeville | Travins J.M.,Collegeville | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRβ binding IC50 values <10 nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC50 values <10 nM and were as efficacious as T0901317. © 2009 Elsevier Ltd. All rights reserved.


Crombie A.L.,Pfizer | Antrilli T.M.,Cardiovascular and Metabolic Diseases Research | Campbell B.A.,Collegeville | Crandall D.L.,Cardiovascular and Metabolic Diseases Research | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V 1a- and good V 2-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V 1a/V 2-receptor antagonist standard. © 2010 Elsevier Ltd.


Bernotas R.C.,Collegeville | Antane S.,Chemical science | Harrison B.L.,Chemical science | Robichaud A.J.,Chemical science | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT6 receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT6 binding affinity with Ki values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC50 = 60 nM, Emax = 70%) and antagonists (6y: IC50 = 17 nM, Imax = 86%) were identified in a 5-HT6 adenylyl cyclase assay. © 2010 Elsevier Ltd. All rights reserved.


Crombie A.L.,Pfizer | Sum F.-W.,Chemical science | Powell D.W.,Chemical science | Hopper D.W.,Chemical science | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of tricyclic anilinopyrimidines were synthesized and evaluated as IKKβ inhibitors. Several analogues, including tricyclic phenyl (10, 18a, 18c, 18d, and 18j) and thienyl (26 and 28) derivatives were shown to have good in vitro enzyme potency and excellent cellular activity. Pharmaceutical profiling of a select group of tricyclic compounds compared to the non-tricyclic analogues suggested that in some cases, the improved cellular activity may be due to increased clog P and permeability. © 2010 Elsevier Ltd.


McCarthy E.D.,U.S. National Institute of Standards and Technology | Zammarano M.,U.S. National Institute of Standards and Technology | Zammarano M.,American University of Washington | Fox D.M.,American University of Washington | And 5 more authors.
Polymer (United Kingdom) | Year: 2013

We report the formation of an ionomeric network in a poly(l,d-lactide) hybrid nanocomposite, (PLDLA-HYB) during in-situ melt polymerization of l,d-lactide in the presence of magnesium/aluminum layered-double-hydroxide (LDH) without added catalyst. The effect of LDH mass loading and reaction time on molecular mass and yield of soluble poly(l,d-lactide) (PLDLA-SOL) present in the hybrid was investigated for a better understanding of the conflicting roles of LDH in polymerization and degradation of PLDLA-SOL. High molecular mass PLDLA-SOL is obtained through initiation of polymerization by LDH. However an additional insoluble organic-inorganic fraction, INSOL, is also observed within the product when PLDLA-SOL is extracted using methylene chloride as solvent. It is proposed that INSOL is an ionomeric network comprising hydrogen-bonded, or otherwise co-ordinated, lactic acid monomer salts of magnesium, together with PLDLA in a 24%-76% mass ratio. © 2012 Elsevier Ltd. All rights reserved.

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