Paul Rowland

article

The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis

John Liddle, Benjamin Beaufils, Margaret Binnie, Anne Bouillot, more

Bioorganic & Medicinal Chemistry Letters > 2017 > 27 > 9 > 2023-2028

A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.

article

BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Brian Clarke, Leanne Cutler, Emmanuel Demont, Colin Dingwall, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 15 > 4639-4644

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.

article

Synthesis and evaluation of novel α-amino cyclic boronates as inhibitors of HCV NS3 protease

Xianfeng Li, Yong-Kang Zhang, Yang Liu, Charles Z. Ding, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 12 > 3550-3556

We have designed and synthesized a novel series of α-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds...

article

Consensual commitment: A grounded theory of the meso-level influence of organizational design on leadership and decision-making

Paul Rowland, Ken Parry

The Leadership Quarterly > 2009 > 20 > 4 > 535-553

This research examined the relationship between organizational design and leadership in decision-making teams. It used a grounded theory-based qualitative research design. The validity of the research was enhanced by data triangulation, wherein quantitative psychometric data augmented the qualitative data that are traditionally used. The research was based upon two organizations within the substantive...

article

Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

Nicolas Charrier, Brian Clarke, Leanne Cutler, Emmanuel Demont, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 13 > 3664-3668

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain...

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Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent

Nicolas Charrier, Brian Clarke, Emmanuel Demont, Colin Dingwall, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 13 > 3669-3673

Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved...

article

Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

Nicolas Charrier, Brian Clarke, Leanne Cutler, Emmanuel Demont, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 13 > 3674-3678

Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy...

article

Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability ^†

Nicolas Charrier, Brian Clarke, Leanne Cutler, Emmanuel Demont, more

Journal of Medicinal Chemistry > 2008 > 51 > 11 > 3313 - 3317

article

BACE-1 inhibitors Part 1: Identification of novel hydroxy ethylamines (HEAs)

Brian Clarke, Emmanuel Demont, Colin Dingwall, Rachel Dunsdon, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 3 > 1011-1016

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based...

article

BACE-1 inhibitors part 3: Identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells

Paul Beswick, Nicolas Charrier, Brian Clarke, Emmanuel Demont, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 3 > 1022-1026

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in...

article

BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced peptidic character

Brian Clarke, Emmanuel Demont, Colin Dingwall, Rachel Dunsdon, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 3 > 1017-1021

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P1′ and P2′ substituents, two different binding modes were observed in X-ray co-crystal structures.

article

N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3

Richard M. Angell, Francis L. Atkinson, Murray J. Brown, Tsu Tshen Chuang, more

Bioorganic & Medicinal Chemistry Letters > 2007 > 17 > 5 > 1296-1301

The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC ₅₀ 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC ₅₀ 6.5). Selectivity within the mitogen-activated protein...

article

Structure of Dihydroorotate Dehydrogenase B - Electron Transfer between Two Flavin Groups Bridged by an Iron-Sulphur Cluster

Paul Rowland, Sofie Nørager, Kaj Frank Jensen, Sine Larsen

Structure > 2000 > 8 > 12 > 1227-1238

Background: The fourth step and only redox reaction in pyrimidine de novo biosynthesis is catalyzed by the flavoprotein dihydroorotate dehydrogenase (DHOD). Based on their sequences, DHODs are grouped into two major families. Lactococcus lactis is one of the few organisms with two DHODs, A and B, belonging to each of the two subgroups of family 1. The B enzyme (DHODB) is a prototype for DHODs in Gram-positive...

article

PAX2 Suppresses Apoptosis in Renal Collecting Duct Cells

Elena Torban, Michael Roger Eccles, Jack Favor, Paul Rowland Goodyer

The American Journal of Pathology > 2000 > 157 > 3 > 833-842

PAX2 is a transcription factor belonging to the evolutionarily conserved paired box family and is required during development of the central nervous system and genitourinary axis. Mutations in the PAX2 gene cause a rare autosomal dominant renal-coloboma syndrome, characterized by optic nerve colobomas and renal hypoplasia. Recent analysis of a spontaneous PAX2 mutant mouse model (1Neu) revealed that...

article

Improvement and the quenched light hadron spectrum and matrix elements

UKQCD, Paul Rowland

Nuclear Physics B (Proceedings Supplements) > 1998 > 63 > 1-3 > 173-175

We present results for the light hadron spectrum and pseudoscalar decay constant in quenched QCD. Our simulations employ the Wilson gauge action, and the Sheikholeslami-Wohlert fermion action with two choices for the clover coefficient: the tadpole-improved value and the non-perturbatively determined value. Simulations are performed at several lattice spacings to enable extrapolations to the continuum...

article

The crystal structure of the flavin containing enzyme dihydroorotate dehydrogenase A from Lactococcus lactis

Paul Rowland, Finn S Nielsen, Kaj Frank Jensen, Sine Larsen

Structure > 1997 > 5 > 2 > 239-252

Background: Dihydroorotate dehydrogenase (DHOD) is a flavin mononucleotide containing enzyme, which catalyzes the oxidation of (S)-dihydroorotate to orotate, the fourth step in the de novo biosynthesis of pyrimidine nucleotides. Lactococcus lactis contains two genes encoding different functional DHODs whose sequences are only 30% identical. One of these enzymes, DHODA, is a highly efficient dimer,...

INFONA - science communication portal

Search results for: Paul Rowland

The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis

BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Synthesis and evaluation of novel α-amino cyclic boronates as inhibitors of HCV NS3 protease

Consensual commitment: A grounded theory of the meso-level influence of organizational design on leadership and decision-making

Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent

Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability ^†

BACE-1 inhibitors Part 1: Identification of novel hydroxy ethylamines (HEAs)

BACE-1 inhibitors part 3: Identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells

BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced peptidic character

N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3

Structure of Dihydroorotate Dehydrogenase B - Electron Transfer between Two Flavin Groups Bridged by an Iron-Sulphur Cluster

PAX2 Suppresses Apoptosis in Renal Collecting Duct Cells

Improvement and the quenched light hadron spectrum and matrix elements

The crystal structure of the flavin containing enzyme dihydroorotate dehydrogenase A from Lactococcus lactis

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