Isis Innovation Limited

Oxford University Innovation Limited

Smithkline Beecham Corporation

Medical Research Council

Ludwig-Maximilians-Universitat München

Christopher Joseph Schofield

Peter John Ratcliffe

Christopher William Pugh

Michael Arnold McDonough

Jürgen Brem

Patrick Henry Maxwell

Matthew Edward Cockman

Joseph Floyd Clark

Kirsty Sarah Hewitson

Wei Ge

Thomas Andrew Daniel Cadoux-Hudson

Keith H Baggaley

Luke McNeill

Jack E Baldwin

Jack Edward Baldwin

Alison Jane Earl

Barry Barton

Philip Stephen Jones

William Henry Holms

David Michael Mousdale

Angus John Morrison

Stephen William Elson

Neville Hubert Nicholson

Jan Edward Thirkettle

Magnus W Walter

Matthew B Avison

Collin W G Fishwick

Ricky Cain

Samuel T Cahill

Jeffrey Edwards

Philip Hinchcliffe

Karina Calvopina

James Spencer

Robert M Adlington

Jean-Marie Frere

Felici Antonio

Peter Brandt

Joanne Hewitt

Tharindi Panduwawala

David Wang

Mounir Andaloussi

Sander S Van Berkel

Mathew Louis Coleman

Alexander Wolf

Armin Thalhammer

Christoph Loenarz

Frances Mary Ashcroft

Christopher Paul Ponting

Thomas Gerken

Nicolas Joseph Jean Granatino

Jonathan Mark Elkins

Norma Masson

Jonathan Mark Gleadle

Heather Jane McNaughton

Anna M Rydzik

Andrew Pannifer

Celia Jane Webby

Michael A Mcdonough

Angelika Boettger

The present invention relates to the use of certain β-lactamase inhibitors in conjunction with one or more ⊕-lactam antibiotics for the treatment oftuberculosis orinfections.

β-lactamase inhibitors

The present invention relates to certain compounds, in particular, indole derivatives that function as inhibitors of bacterial metallo-beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection.

Inhibitors of metallo-beta-lactamases

The present invention relates to compounds of Formula (I) that function as inhibitors of bacterial metallo-beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection. (Formula (I)) 

A compound which is a thienolate of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein R, R, Ring A1, n and Ring A2 are as defined herein, are found to be useful in inhibiting metallo-beta-lactamase and therefore in potentiating the activity of beta lactamase antibiotics. The compound can be used alone or in combination with a rhodanine of formula (II) or a pharmaceutically acceptable salt thereof: (II) wherein R, Ring A1, n, Ring A2, L and Ring B are as defined herein. Treatment or prevention of bacterial infection in combination with beta-lactam antibiotic agents is also provided. 

Beta lactamase inhibitors

A novel class of hydroxylases is described having the amino acid sequence of SEQ ID NO: 2, 4, 6 and 8, and variants and fragments thereof having HIF hydroxylation activity. The polypeptides of the invention have in particular prolyl hydroxylase activity. An assay method monitors the interaction of the HIF hydroxylase with a substrate. Modulators of HIF hydroxylase are provided for use in the treatment of a condition associated with increased or decreased HIF levels or activity or for the treatment of a condition where it is desirable to modulate HIF levels or activity.

Antibody against human HIF hydroxylase

The present invention relates to assays for monitoring activity of Mina53 and NO66 activities, in particular, to assays for identifying modulators of Mina53 and NO66 activities. The invention also relates to assays to monitor the histidinyl hydroxylase activity of Mina53 and NO66 on their substrates, the human ribosomal protein Rpl27a and Rpl8 respectively. The invention also enables the introduction of S-3-hydroxyhistidinyl residues into peptides and proteins.

Assay for histidinyl hydroxylase activity

The present invention relates to assays for monitoring activity of OGFOD1 activity, in particular, to assays for identifying modulators of OGFOD1 activity. The invention also relates to assays to monitor the prolyl hydroxylase activity of OGFOD1 on its substrate, the human ribosomal protein RPS23. The invention also enables the introduction of 3-hydroxyprolyl residues into peptides and proteins.

Method for assaying OGFOD1 activity

Assay for identifying a modulator of HIF hydroxylase

The present invention provides a method for assaying oxygenase activity, the method comprising monitoring oxygenase activity of FTO.

Method for assaying FTO (2-oxoglutarate dependent oxygenase) activity

The present invention comprises a method for assaying oxygenase activity the method comprising monitoring oxygenase activity of Mina53.

Mina53 assays

A method of identifying, screening, characterising or designing a chemical entity, which mimics or binds to FIH, is described. The method comprises comparing a structural model of FIH with a structural model for said chemical entity, wherein said structural model of FIH is derived from structural factors or structural coordinates determined by subjecting to X-ray diffraction measurements a crystal comprising FIH. Such chemical entities may be used in the treatment of a condition associated with increased or decreased HIF levels or activity.

Method of identifying a chemical entity which is a hydroxylase modulator

The invention provides a compound of one of the formulae (A), (B), (C), (D), (E), (F) as herein defined, or a salt thereof, for use in the treatment of a condition associated with increased or decreased HIF levels or activity, or a condition in which an increase or decrease in HIF levels or activity may be beneficial. 

HIF hydroxylase inhibitors

A method of identifying an agent which modulates 2-oxoglutarate dependent oxygenase activity, the method comprising contacting a 2-oxoglutarate dependent oxygenase and a test agent in the presence of a substrate comprising one or more ankyrin repeat, or fragment thereof, in conditions under which the substrate is hydroxylated in the absence of the test agent; and determining hydroxylation of the substrate.

Assays for identifying modulators of the hydroxylation of ankyrin repeat proteins by 2-oxoglutarate dependent oxygenase and methods of using the same

A method of identifying an agent which modulates hydroxylation of hypoxia inducible factor (HIF), comprises contacting a HIF asparagine hydroxylase and a test substance in the presence of a substrate of the hydroxylase under conditions in which asparagine in the substrate is hydroxylated in the absence of the test substance; and determining hydroxylation of the substrate. Preferably the substrate is a HIF polypeptide comprising HIF-1&#x3b1;, a fragment thereof comprising Asn 803 of HIF-1&#x3b1; or a peptide analogue of HIF-1&#x3b1; or fragment thereof comprising an asparagine equivalent to Asn 803 of HIF-1&#x3b1; and wherein hydroxylation of Asn 803 or of a said equivalent asparagine is determined.

Assays for modulators of asparaginyl hydroxylase

A pharmaceutical composition comprising a compound of formula (I) wherein X is an electron withdrawing group, Yis hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, &#x2014;SOR, &#x2014;COR, &#x2014;CONHRor &#x2014;COR, and each of R, Rand R, which may be the same or different, is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or heterocyclyl, or a compound of formula (II) wherein each of Yand Y, which may be the same or different, is hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, &#x2014;SOR, &#x2014;COR, &#x2014;CONHRor &#x2014;COR, Z is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, &#x2014;CH&#x2550;C(NHR)CH((CH)m COR)(C&#x2550;O)CHor &#x2014;CH(C&#x2550;O)CH((CH)COR)(C&#x2550;O)CH, Ris &#x2014;(CH)COR, each of Rto Rand Rto R, which may be the same or different, is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or heterocyclyl, and each of m and n, which may be the same or different, is 1 to 6 or a compound of formula (III) wherein each of Yto Y, which may be the same or different, is hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, &#x2014;SOR, &#x2014;COR, &#x2014;CONHRor &#x2014;COR, each of Rand R, which may be the same or different, is &#x2014;(CH)p COR, each of Rto Rand Rto R, which may be the same or different, is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or heterocyclyl, and p is 1 to 6, or other photolabile degradation product of bilirubin or biliverdin or derivative of a photolabile degradation fragment of bilirubin or biliverdin, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

Degradation fragments

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Oxford, United Kingdom

Christopher Joseph Schofield