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Publication


Featured researches published by Linos Lazarides.


Bioorganic & Medicinal Chemistry Letters | 2010

Synthesis and Evaluation of Novel Alpha-Amino Cyclic Boronates as Inhibitors of Hcv Ns3 Protease.

Xianfeng Li; Yong-Kang Zhang; Yang Liu; Charles Z. Ding; Qun Li; Yasheen Zhou; Jacob J. Plattner; Stephen J. Baker; Xuelei Qian; Dazhong Fan; Liang Liao; Zhi-Jie Ni; Gemma Victoria White; Jackie E. Mordaunt; Linos Lazarides; Martin John Slater; Richard L. Jarvest; Pia Thommes; Malcolm Ellis; Colin M. Edge; Julia A. Hubbard; Don O. Somers; Paul Rowland; Pamela Nassau; Bill McDowell; Tadeusz Skarzynski; Wieslaw M. Kazmierski; Richard Martin Grimes; Lois L. Wright; Gary K. Smith

We have designed and synthesized a novel series of alpha-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 are described.


Journal of Medicinal Chemistry | 2016

Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma.

Keith Biggadike; Mahbub Ahmed; Doug I. Ball; Diane Mary Coe; Deidre Dalmas Wilk; Chris D. Edwards; Bob H. Gibbon; Charlotte J. Hardy; Stephen A. Hermitage; Joanne O. Hessey; Aimee Hillegas; Stephen C. Hughes; Linos Lazarides; Xiao Qing Lewell; Amanda Lucas; David N. Mallett; Mark Price; Fiona Priest; Diana Quint; Poonam Shah; Anesh Sitaram; Stephen A. Smith; Richard Stocker; Naimisha Trivedi; Daphne Tsitoura; Victoria Weller

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.


Journal of Medicinal Chemistry | 2017

Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A

Victoria Alexandra Steadman; Simon B. Pettit; Karine G. Poullennec; Linos Lazarides; Andrew John Keats; David Kenneth Dean; Steven James Stanway; Carol Austin; Jonathan Sanvoisin; Gregory M. Watt; Hans Fliri; Albert Liclican; Debi Jin; Melanie H. Wong; Stephanie A. Leavitt; Yu-Jen Lee; Yang Tian; Christian R. Frey; Todd C. Appleby; Uli Schmitz; Petr Jansa; Richard L. Mackman; Brian E. Schultz

Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.


Journal of Medicinal Chemistry | 2018

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

Richard L. Mackman; Victoria Alexandra Steadman; David Kenneth Dean; Petr Jansa; Karine G. Poullennec; Todd C. Appleby; Carol Austin; Caroline A Blakemore; Ruby Cai; Carina E. Cannizzaro; Gregory Chin; Jean-Yves Christophe Chiva; Neil Andrew Dunbar; Hans Fliri; Adrian J. Highton; Hon C. Hui; Mingzhe Ji; Haolun Jin; Kapil Karki; Andrew John Keats; Linos Lazarides; Yu-Jen Lee; Albert Liclican; Michael R. Mish; Bernard P. Murray; Simon B. Pettit; Peter Pyun; Michael Sangi; Rex Santos; Jonathan Sanvoisin

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.


Archive | 2008

PURINE DERIVATIVES AS IMMUNOMODULATORS

Linos Lazarides; Stephen A. Smith; Richard Stocker; Colin J. Theobald


Archive | 2006

C (2) -heteroarylmethyl-c (4) -pyrazinyl-2-yl acyl pyrrolidine compounds and their use for treating viral infections, especially hepatitis c virus

David Haigh; Charles David Hartley; Peter D. Howes; Linos Lazarides; F. Nerozzi; Stephen A. Smith


Archive | 2009

Novel adenine derivatives

Helene Bazin-Lee; Diane Mary Coe; Linos Lazarides; Charlotte Jane Mitchell; Stephen A. Smith; Naimisha Trivedi


Archive | 2008

Novel cyclic boronate inhibitors of hcv replication

Dazhong Fan; Richard L. Jarvest; Linos Lazarides; Qun Li; Xianfeng Li; Yang Liu; Liang Liao; Jacqueline Elizabeth Mordaunt; Zhi-Jie Ni; Jacob J. Plattner; Xuelei Qian; Martin John Slater; Gemma Victoria White; Yong Kang Zhang


Archive | 2013

Macrocyclic inhibitors of flaviviridae viruses

Caroline Aciro; Victoria Alexandra Steadman; Simon Neil Pettit; Karine G. Poullennec; Linos Lazarides; David Kenneth Dean; Neil Andrew Dunbar; Adrian J. Highton; Andrew John Keats; Dustin Siegel; Kapil Karki; Adam James Schrier; Petr Jansa; Richard L. Mackman


Archive | 2006

Pyrrolidine derivatives for treating viral infections

David Haigh; Charles David Hartley; Peter D. Howes; Linos Lazarides; F. Nerozzi; Stephen A. Smith

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F. Nerozzi

University of California

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Richard Stocker

University of Hertfordshire

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Petr Jansa

Academy of Sciences of the Czech Republic

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