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From Structure to Clinic: Discovery of A M1 Muscarinic Acetylcholine Receptor Agonist for the Treatment of Memory Loss in Alzheimer's Disease

113 Pages Posted: 29 Jul 2020 Publication Status: Review Complete

See all articles by Alastair J. H. Brown

Alastair J. H. Brown

Sosei Heptares

Sophie J. Bradley

University of Glasgow

Giles A. Brown

Sosei Heptares

Kirstie A. Bennett

Sosei Heptares

Jason Brown

Sosei Heptares

Julie E. Cansfield

Sosei Heptares

David M. Cross

Sosei Heptares

João M. Dias

Sosei Heptares

James C. Errey

Sosei Heptares

Edward Hurrell

Sosei Heptares

Jan Liptrot

Sosei Heptares

Colin Molloy

University of Glasgow

Pradeep J. Nathan

Sosei Heptares

Krzysztof Okrasa

Sosei Heptares

Greg Osbourne

Sosei Heptares

Jayesh C. Patel

Sosei Heptares

Mark Pickworth

Sosei Heptares

Nathan Robertson

OXGENE Biotechnology

Shahram Shahabi

Eli Lilly & Co - Neuroscience Discovery

Christoffer Bundgaard

Eli Lilly & Co - Neuroscience Discovery

Keith Phillips

Eli Lilly & Co - Neuroscience Discovery

Lisa M. Broad

Eli Lilly & Co - Neuroscience Discovery

Anushka V. Goonawardena

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Stephen R. Morairty

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Michael Browning

University of Oxford

Francesca Perini

Duke-NUS Medical School

Gerard R. Dawson

University of Oxford - Department of Psychiatry

John F. W. Deakin

University of Manchester

Robert T. Smith

Sosei Heptares

Patrick M. Sexton

Monash University - Monash Institute of Pharmaceutical Sciences

Julie Warneck

Protogenia Consulting, Ltd.

Mary Vinson

Sosei Heptares

Tim Tasker

Sosei Heptares

Benjamin G. Tehan

Sosei Heptares

Barry Teobald

Sosei Heptares

Arthur Christopoulos

Monash University - Monash Institute of Pharmaceutical Sciences

Christopher J. Langmead

Monash University - Monash Institute of Pharmaceutical Sciences

Ali Jazayeri

Sosei Heptares

Robert M. Cooke

Sosei Heptares

Fiona H. Marshall

Sosei Heptares

Prakash Rucktooa

Sosei Heptares

Miles S. Congreve

Sosei Heptares

Malcolm Weir

Sosei Heptares

Andrew Tobin

University of Glasgow - Institute of Molecular, Cell and Systems Biology

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Abstract

Current therapies for improving memory in Alzheimer’s disease are focused on correcting for defective cholinergic transmission by increasing acetylcholine levels through inhibition of acetylcholinesterase enzymes. These treatments are however associated with limited clinical efficacy and dose-limiting adverse effects. Here we describe agonist-bound crystal structures of the M1 muscarinic acetylcholine receptor (M1 mAChR) and its application in supporting the rational drug design of a selective M1-orthosteric agonist, HTL0009936. On the basis of pro-cognitive effects across a range of pre-clinical animal models and a favourable safety and toxicology profile HTL0009936 was progressed to first in human trials where the agonist activated central processes corresponding to learning and memory circuitry. Hence, our study not only describes the pharmacological profile of a M1 mAChR agonist with the potential to improve memory in Alzheimer’s disease but also demonstrates how to rationally progress the development of a G protein-coupled receptor ligand from structure to clinical candidate.

Suggested Citation

Brown, Alastair J. H. and Bradley, Sophie J. and Brown, Giles A. and Bennett, Kirstie A. and Brown, Jason and Cansfield, Julie E. and Cross, David M. and Dias, João M. and Errey, James C. and Hurrell, Edward and Liptrot, Jan and Molloy, Colin and Nathan, Pradeep J. and Okrasa, Krzysztof and Osbourne, Greg and Patel, Jayesh C. and Pickworth, Mark and Robertson, Nathan and Shahabi, Shahram and Bundgaard, Christoffer and Phillips, Keith and Broad, Lisa M. and Goonawardena, Anushka V. and Morairty, Stephen R. and Browning, Michael and Perini, Francesca and Dawson, Gerard R. and Deakin, John F. W. and Smith, Robert T. and Sexton, Patrick M. and Warneck, Julie and Vinson, Mary and Tasker, Tim and Tehan, Benjamin G. and Teobald, Barry and Christopoulos, Arthur and Langmead, Christopher J. and Jazayeri, Ali and Cooke, Robert M. and Marshall, Fiona H. and Rucktooa, Prakash and Congreve, Miles S. and Weir, Malcolm and Tobin, Andrew, From Structure to Clinic: Discovery of A M1 Muscarinic Acetylcholine Receptor Agonist for the Treatment of Memory Loss in Alzheimer's Disease. Available at SSRN: https://ssrn.com/abstract=3641933 or http://dx.doi.org/10.2139/ssrn.3641933
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Alastair J. H. Brown

Sosei Heptares ( email )

Sophie J. Bradley

University of Glasgow

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Giles A. Brown

Sosei Heptares

Kirstie A. Bennett

Sosei Heptares ( email )

Jason Brown

Sosei Heptares ( email )

Julie E. Cansfield

Sosei Heptares ( email )

David M. Cross

Sosei Heptares ( email )

João M. Dias

Sosei Heptares ( email )

James C. Errey

Sosei Heptares ( email )

Edward Hurrell

Sosei Heptares ( email )

Jan Liptrot

Sosei Heptares ( email )

Colin Molloy

University of Glasgow

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Pradeep J. Nathan

Sosei Heptares ( email )

Krzysztof Okrasa

Sosei Heptares ( email )

Greg Osbourne

Sosei Heptares ( email )

Jayesh C. Patel

Sosei Heptares ( email )

Mark Pickworth

Sosei Heptares ( email )

Nathan Robertson

OXGENE Biotechnology ( email )

Shahram Shahabi

Eli Lilly & Co - Neuroscience Discovery ( email )

Christoffer Bundgaard

Eli Lilly & Co - Neuroscience Discovery ( email )

Keith Phillips

Eli Lilly & Co - Neuroscience Discovery ( email )

Lisa M. Broad

Eli Lilly & Co - Neuroscience Discovery ( email )

Anushka V. Goonawardena

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Panama

Stephen R. Morairty

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Panama

Michael Browning

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Francesca Perini

Duke-NUS Medical School

Gerard R. Dawson

University of Oxford - Department of Psychiatry ( email )

Warneford Hospital
Warneford Ln
Oxford, OX3 7JX
United Kingdom

John F. W. Deakin

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Robert T. Smith

Sosei Heptares ( email )

Patrick M. Sexton

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Julie Warneck

Protogenia Consulting, Ltd. ( email )

Mary Vinson

Sosei Heptares ( email )

Tim Tasker

Sosei Heptares ( email )

Benjamin G. Tehan

Sosei Heptares ( email )

Barry Teobald

Sosei Heptares ( email )

Arthur Christopoulos

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Christopher J. Langmead

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Ali Jazayeri

Sosei Heptares ( email )

Robert M. Cooke

Sosei Heptares ( email )

Fiona H. Marshall

Sosei Heptares ( email )

Prakash Rucktooa

Sosei Heptares ( email )

Miles S. Congreve

Sosei Heptares ( email )

Malcolm Weir

Sosei Heptares ( email )

Andrew Tobin (Contact Author)

University of Glasgow - Institute of Molecular, Cell and Systems Biology ( email )

Glasgow
United Kingdom

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