Long-Range Inhibitor-Induced Conformational Regulation of Human IRE1α Endoribonuclease Activity.

Activation of the inositol-requiring enzyme-1 alpha (IRE1α) protein caused by endoplasmic reticulum stress results in the homodimerization of the N-terminal endoplasmic reticulum luminal domains, autophosphorylation of the cytoplasmic kinase domains, and conformational changes to the cytoplasmic endoribonuclease (RNase) domains, which render them functional and can lead to the splicing of X-box binding protein 1 (XBP 1) mRNA. Herein, we report the first crystal structures of the cytoplasmic portion of a human phosphorylated IRE1α dimer in complex with (R)-2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2,7-diazaspiro(4.5)decane-7-carboxamide, a novel, IRE1α-selective kinase inhibitor, and staurosporine, a broad spectrum kinase inhibitor.

Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels.

Background: Huntington's disease (HD) is a late-onset fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene coding for the protein huntingtin and is characterised by progressive motor, psychiatric and cognitive decline. We previously demonstrated that normal synaptic function in HD could be restored by application of dopamine receptor agonists, suggesting that changes in the release or bioavailability of dopamine may be a contributing factor to the disease process.

Objective: In the present study, we examined the properties of midbrain dopaminergic neurones and dopamine release in presymptomatic and symptomatic transgenic HD mice.

Novel synthesis of 5-amino-3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbonitrile: a versatile intermediate for the preparation of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides.

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.

Assessing the knowledge of the potential harm to others caused by second-hand smoke and its impact on protective behaviours at home.

Background: Smokers' knowledge of the risks of second-hand smoke (SHS) and the role this plays in implementing behaviours to reduce the SHS exposure of others have not been thoroughly explored. Mass media health promotion is used to promote behaviour change partly by providing information on the consequences of behaviour. In England, between 2003 and 2006, frequent mass media campaigns highlighted the toxicity of SHS.

Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.

A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.

3-Urea-1-(phenylmethyl)-pyridones as novel, potent, and selective EP3 receptor antagonists.

A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described.

The prescribed duration algorithm: utilising 'free text' from multiple primary care electronic systems.

Purpose: To develop and test an algorithm that translates total dose and daily regimen, inputted as 'free text' on a prescription, into numerical values to calculate the prescribed treatment duration.

Method: The algorithm was developed using antibiotic prescriptions (n = 711,714) from multiple primary care computer systems. For validation, the prescribed treatment duration of an independent sample of antibiotic scripts was calculated in two ways: (a) computer algorithm, (b) manually reviewed by a researcher blinded to the results of (a).

Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists.

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.

Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists.

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.

Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors.

A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.

Synthesis and structure-activity relationships of 3-phenyl-2-propenamides as inhibitors of glycogen phosphorylase a.

A series of 3-phenyl-2-propenamides discovered from a high-throughput screening campaign as novel, potent, glucose-sensitive inhibitors of human liver glycogen phosphorylase a is described. A solid-phase synthesis on DMHB resin was also developed which provided efficient access not only to certain analogues that could not be cleanly made using more traditional means, but also to a variety of additional analogues. The SAR scope and synthetic strategy are presented herein.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented.

Synthesis of biotin conjugates of the antifungal compound cymoxanil.

Biotin conjugates are of considerable value in investigating the mode of action of biologically active compounds. Two biotin conjugates related to the antifungal compound cymoxanil [1-(2-cyano-2-methoximinoacetyl)-3-ethyl urea] were prepared as the first step in an effort to employ display cloning to identify the compound's target site. In the first conjugate, prepared in five steps, the biotin moiety was attached at the position occupied by the ethyl group in cymoxanil.