Kurt R Stover, Paul M Stafford, Andreea C Damian, Jagadeesh P Pasangulapati, Jake Goodwin-Tindall, Lucía M López Vásquez, Sanghyun Lee, Seung-Pil Yang, Mark A Reed, Christopher J Barden, Donald F Weaver
{"title":"Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.","authors":"Kurt R Stover, Paul M Stafford, Andreea C Damian, Jagadeesh P Pasangulapati, Jake Goodwin-Tindall, Lucía M López Vásquez, Sanghyun Lee, Seung-Pil Yang, Mark A Reed, Christopher J Barden, Donald F Weaver","doi":"10.2174/0115672050283199240111111801","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.</p><p><strong>Methods: </strong>To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.</p><p><strong>Results: </strong>We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound.</p><p><strong>Conclusion: </strong>This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Alzheimer research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/0115672050283199240111111801","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.
Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.
Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound.
Conclusion: This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
