Rama Jain, Mark Knapp, Sarah E. Kochanek, Adam Lewis, Lynn M. McGregor, Vanja Stojkovic, Jenny Tang, Tiffany Tsang, Kelly Yan, Aregahegn Yifru, Qingming Zhu, Francesca Fabbiani, Gu Feng, Andreas O. Frank, John Fuller, Wolfgang Jahnke, Johanna M. Jansen, Jihye Jo, Min Li, Jennifer Lipps, Yipin Lu, Tim Mladenovic, Philippe Piechon, Phuong Rogemoser, Feng Wang, Shengtian Yang, Colin K. Skepper
{"title":"Covalent Stabilizers of the Interaction Between 14-3-3σ and Estrogen Receptor-α","authors":"Rama Jain, Mark Knapp, Sarah E. Kochanek, Adam Lewis, Lynn M. McGregor, Vanja Stojkovic, Jenny Tang, Tiffany Tsang, Kelly Yan, Aregahegn Yifru, Qingming Zhu, Francesca Fabbiani, Gu Feng, Andreas O. Frank, John Fuller, Wolfgang Jahnke, Johanna M. Jansen, Jihye Jo, Min Li, Jennifer Lipps, Yipin Lu, Tim Mladenovic, Philippe Piechon, Phuong Rogemoser, Feng Wang, Shengtian Yang, Colin K. Skepper","doi":"10.1021/acsmedchemlett.6c00325","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00325","url":null,"abstract":"<p>Selective stabilization of complexesformed by the hub protein14-3-3 represents an emerging mechanism for the modulation of therapeuticallyrelevant targets. In this letter, we describe a hit-finding campaigndesigned to identify small molecule stabilizers of the interactionbetween 14-3-3σ and the estrogen receptor alpha (ERα).Four structurally distinct hits were identified and validated usinga combination of biochemical assays and biophysical techniques. Ternarycomplex crystal structures revealed that all four hit compounds forma covalent bond with Cys38 of 14-3-3σ via four different electrophilicwarheads. Structure-based optimization of the most promising hit compound <strong>9</strong> led to dramatic improvements in stabilization activity andselectivity that exceeded the complex natural product fusicoccin A.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2006–2016"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Bridged Tricyclic Carbamoylpyridone Compounds as HIV Integrase Inhibitors for Treating HIV Infection","authors":"Ram W. Sabnis","doi":"10.1021/acsmedchemlett.6c00431","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00431","url":null,"abstract":"<p>Provided herein are novel bridgedtricyclic carbamoylpyridonecompoundsas HIV integrase inhibitors, pharmaceutical compositions, use of suchcompounds in treating HIV infection, and processes for preparing suchcompounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1939–1940"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shaoyi Sun, Qi Jia, Girish Bankar, Kristen N. Burford, Jessica Christabel, Helen A. Clement, Gina de Boer, Zirui Feng, Chido M. Hambira, Stephen K. Jackson, Kuldip Khakh, Rainbow Kwan, Stephanie Lee, Jenny Li, Andrea Lindgren, Janette Mezeyova, Juliette Sabbatini, Art Urrutia, Paul Charifson, Michael P. Clark, Steven S. Wesolowski, James P. Johnson, Jr., James R. Empfield, Christoph M. Dehnhardt, Richard Dean
{"title":"Discovery of Novel Bicyclic Pyrazole Amides as Potent Neuronal KV7 Potassium Channel Openers with Strong Preclinical Antiseizure Activity","authors":"Shaoyi Sun, Qi Jia, Girish Bankar, Kristen N. Burford, Jessica Christabel, Helen A. Clement, Gina de Boer, Zirui Feng, Chido M. Hambira, Stephen K. Jackson, Kuldip Khakh, Rainbow Kwan, Stephanie Lee, Jenny Li, Andrea Lindgren, Janette Mezeyova, Juliette Sabbatini, Art Urrutia, Paul Charifson, Michael P. Clark, Steven S. Wesolowski, James P. Johnson, Jr., James R. Empfield, Christoph M. Dehnhardt, Richard Dean","doi":"10.1021/acsmedchemlett.6c00360","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00360","url":null,"abstract":"<p>Therehas been considerable interest in developing openersof neuronalK<sub>V</sub>7 potassium channels, particularly K<sub>V</sub>7.2 (KCNQ2)and K<sub>V</sub>7.3 (KCNQ3), as both genetic and clinical evidencestrongly support their therapeutic potential in seizure disorders.Herein, we describe the discovery of a series of neuronal K<sub>V</sub>7 potassium channel openers, optimized primarily via conformationalrigidification and carbon to oxygen replacement. The combination ofthese structural modifications, together with careful investigationof the structure–activity relationship (SAR), culminated inthe discovery of <strong><em>S</em>-35</strong>, a potent andmetabolically stable neuronal K<sub>V</sub>7 opener that demonstratedfavorable pharmacokinetics (PK) in preclinical species and robustantiseizure efficacy in rodent alternating-current maximal electroshockseizure (AC-MES) assays.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2027–2037"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jason A. Witek, Avery C. Allen, Allen F. Brooks, Shelbie J. Cingoranelli, Jenelle Stauff, Tanpreet Kaur, Xia Shao, Peter J. H. Scott, David M. Raffel
{"title":"Modified Reaction Conditions for the Radiosynthesis of 11C-Labeled Asymmetrical Guanidines and the Automated Radiosynthesis of a [11C]mIBG Analog","authors":"Jason A. Witek, Avery C. Allen, Allen F. Brooks, Shelbie J. Cingoranelli, Jenelle Stauff, Tanpreet Kaur, Xia Shao, Peter J. H. Scott, David M. Raffel","doi":"10.1021/acsmedchemlett.6c00226","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00226","url":null,"abstract":"<p>Radiolabeled guanidines such as <sup>123/131</sup>I-labeled <em>meta</em>-iodobenzylguanidine (<em>m</em>IBG) have beenwidely used in nuclear medicine for imaging of cardiac sympatheticnerves, as well as imaging and treatment of neuroendocrine tumors.For a variety of reasons (e.g., low tumor uptake, suboptimal kinetics),there is a need for second generation guanidines, and the synthesisand evaluation of such radiopharmaceuticals is a long-standing focusof our group. However, to date, the generation of analogues has beenlimited to other monosubstituted guanidines, while both symmetricaland asymmetrical disubstituted analogues around the guanidine havebeen largely ignored because of their synthetic challenges. To addressthis limitation, herein we report general conditions for the synthesisof carbon-11 radiolabeled asymmetric guanidines and show proof-of-conceptthrough the automated radiosynthesis and preclinical evaluation ofa novel <em>m</em>IBG analogue.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1948–1955"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Changho Han, Upendra Rathnayake, Alison R. Gregro, Julie L. Engers, Christopher C. Presley, Nathan D. Schley, Analisa D. Thompson Gray, Michael Bubser, Hyekyung P. Cho, Alice L. Rodriguez, Valerie M. Kramlinger, Olivier Boutaud, Colleen M. Niswender, Carrie K. Jones, Darren W. Engers, Craig W. Lindsley
{"title":"De Novo Design in an M1 Positive Allosteric Modulator Backup Program: The Discovery of VU6069863","authors":"Changho Han, Upendra Rathnayake, Alison R. Gregro, Julie L. Engers, Christopher C. Presley, Nathan D. Schley, Analisa D. Thompson Gray, Michael Bubser, Hyekyung P. Cho, Alice L. Rodriguez, Valerie M. Kramlinger, Olivier Boutaud, Colleen M. Niswender, Carrie K. Jones, Darren W. Engers, Craig W. Lindsley","doi":"10.1021/acsmedchemlett.6c00392","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00392","url":null,"abstract":"<p>Recently, we disclosed our M<sub>1</sub> PAM that hadadvancedinto Phase I clinical studies, VU0467319, as well as a deuteratedback-up compound, VU6045422, to address a major metabolite producedin man and improve tox profile. Ultimately, this series failed toovercome its liabilities and was terminated. However, the team waschallenged with developing chemically distinct backup candidates withoutperforming a new HTS campaign. <em>De novo</em> design strategiesbased upon the other two M<sub>1</sub> ago-PAMs that had previouslyentered clinical development, MK-7622 and TAK-071, led to the discoveryof a fundamentally new chemotype based on a 3,4-dihydrobenzo[<em>f</em>][1,4]oxazepin-5-(<em>2H</em>)-one core, providingVU6069863. VU6069863 proved to be an M<sub>1</sub> PAM (EC<sub>50</sub> = 248 nM, 87% ACh Max) with minimal M<sub>1</sub> agonism, (EC<sub>50</sub> > 30 μM, 19% ACh Max) despite being derived frompotentM<sub>1</sub> ago-PAM chemotypes, with good CNS penetration (rat K<sub>p</sub> = 0.59, K<sub>p,uu</sub> = 0.13, MDCK-MDR1 ER = 1.8, P<sub>app</sub> = 32.8 × 10<sup>–6</sup> cm/s) and pro-cognitiveefficacy in both contextual fear conditioning (minimally effectivedose [MED] = 0.1 mg/kg PO) and novel object recognition (MED = 1 mg/kgPO) in rats.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2085–2094"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
John M. Hatcher, Shirong Liu, Xia Liu, Amanda Kofides, Alexa G. Canning, Dominic Pizzarella, Nickolas Tsakmaklis, Maria L. Guerrera, Christopher J. Patterson, Alberto Guijosa, Prafulla Gokhale, Zachary R Hunter, Shayna R Sarosiek, Jorge J. Castillo, Jinhua Wang, Sara J. Buhrlage, Steven P. Treon
{"title":"Discovery of JH-XIII-05-01, a First-in-Class Dual IRAK1/IRAK4 Degrader for MYD88 Mutant Lymphomas","authors":"John M. Hatcher, Shirong Liu, Xia Liu, Amanda Kofides, Alexa G. Canning, Dominic Pizzarella, Nickolas Tsakmaklis, Maria L. Guerrera, Christopher J. Patterson, Alberto Guijosa, Prafulla Gokhale, Zachary R Hunter, Shayna R Sarosiek, Jorge J. Castillo, Jinhua Wang, Sara J. Buhrlage, Steven P. Treon","doi":"10.1021/acsmedchemlett.6c00276","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00276","url":null,"abstract":"<p>Activating MYD88 mutations promote pro-survival signalingthroughdivergent HCK/BTK and IRAK1/IRAK4 pathways, and persistent IRAK signalingmay contribute to incomplete responses to BTK inhibitors. Here, weshow that IRAK1 or IRAK4 knockdown reduced NFKB signaling and impairedMYD88 mutant lymphoma cell survival but, unexpectedly, enhanced ERK1/2signaling, which was blocked by HCK/BTK inhibition. Knockdown andreplacement studies further supported kinase-independent scaffoldfunctions for IRAK1 and IRAK4. These findings motivated developmentof JH-XIII-05-01, a first-in-class dual IRAK1/IRAK4 degrader designedto eliminate both catalytic and scaffold-dependent IRAK signaling.JH-XIII-05-01 retained potent IRAK1/IRAK4 biochemical activity, induceddegradation of both targets, and showed superior antiproliferativeactivity compared with its nondegrading parental inhibitor JH-XI-82-01.JH-XIII-05-01 also enhanced apoptosis and synergized with covalentand noncovalent BTK inhibitors, BTK degraders, and the BCL-2 inhibitorvenetoclax. These findings support dual IRAK1/IRAK4 degradation asa strategy for targeting MYD88 mutant lymphomas.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1977–1988"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandra Feoli, Giulio Esposito, Manuela Grimaldi, Monica Viviano, Ida Pacilio, Josef Krátký, Anna Maria D’Ursi, Ciro Milite, Haitao Li, Mark T. Bedford, Sabrina Castellano, Gianluca Sbardella
{"title":"Discovery of High-Affinity Peptide Ligands Targeting the SPIN1 Tudor 3 Domain Via a Minimalist Pruning Strategy","authors":"Alessandra Feoli, Giulio Esposito, Manuela Grimaldi, Monica Viviano, Ida Pacilio, Josef Krátký, Anna Maria D’Ursi, Ciro Milite, Haitao Li, Mark T. Bedford, Sabrina Castellano, Gianluca Sbardella","doi":"10.1021/acsmedchemlett.6c00384","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00384","url":null,"abstract":"<p>Spindlin1 (SPIN1) is an epigenetic reader involved inoncology,whose third Tudor domain remains largely underexplored. Here, we applieda minimalist pruning strategy to the 26-mer peptide DOCpep3 to identifythe core pharmacophore for SPIN1 Tudor 3 domain binding. This yieldedtruncated linear peptide analogues (e.g., <strong>1</strong>, <strong>3</strong>, and <strong>4</strong>) displaying low nanomolar affinities, significantlyoutperforming the parent peptide. Orthogonal biophysical validation(MST and SPR) confirmed competitive target engagement. Furthermore,circular dichroism spectroscopy revealed that these pruned ligandsinduce distinct structural rearrangements in SPIN1, establishing high-affinitychemical probes for drug discovery.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2066–2073"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Tetrahydropyridinyl-6,6-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches","authors":"Ram W. Sabnis, Anika R. Sabnis","doi":"10.1021/acsmedchemlett.6c00430","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00430","url":null,"abstract":"<p>Provided herein are novel tetrahydropyridinyl-6,6-bicycliccompoundsas 5-HT2A receptor agonists, pharmaceutical compositions, use of suchcompounds in treating depression, anxiety, substance abuse and headaches,and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1937–1938"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leonard Barasa, Yongzhi Chen, Ala M. Shaqra, Syeda F. Z. Adnan, Lauren E. Intravaia, Sandeep Huchaiah, Akumalla Allabaji, Karthik Kumar S, Srinivasa Rao Vidadala, Santoshkumar N. Patil, Jeffrey Hale, Celia A. Schiffer, Katherine A. Fitzgerald, Paul R. Thompson
{"title":"Nitrile-Based Inhibitors Targeting both SARS-CoV-2 Main Protease and Human Cathepsin L","authors":"Leonard Barasa, Yongzhi Chen, Ala M. Shaqra, Syeda F. Z. Adnan, Lauren E. Intravaia, Sandeep Huchaiah, Akumalla Allabaji, Karthik Kumar S, Srinivasa Rao Vidadala, Santoshkumar N. Patil, Jeffrey Hale, Celia A. Schiffer, Katherine A. Fitzgerald, Paul R. Thompson","doi":"10.1021/acsmedchemlett.6c00236","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00236","url":null,"abstract":"<p>The SARS-CoV-2 mainprotease (M<sup>pro</sup>) and hostcysteineprotease cathepsin L (CatL) are both attractive targets for antiviralintervention. Herein we describe the rational design and synthesisof dual M<sup>pro</sup>/CatL inhibitors derived from the previouslyreported leads <strong>SM141</strong> and <strong>SM142</strong>. Optimizationfocused on replacement of the acrylate ester warhead in <strong>SM141</strong> and <strong>SM142</strong> with a nitrile, modifying the P2, P3, andP4 capping groups, and variation of the P1 lactam ring size. In addition,conformational restriction was achieved through macrocyclization betweenthe P1 and P4 side chains to enhance binding affinity. These effortsidentified multiple dual-target inhibitors with nanomolar potencyagainst both M<sup>pro</sup> and CatL and potent antiviral activityas well as selective M<sup>pro</sup> inhibitors with strong enzymaticactivity. Targeting both a viral protease and a host factor may providemore durable antiviral efficacy by reducing susceptibility to resistancearising from viral evolution of M<sup>pro</sup>.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1956–1965"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caleb A. Jones, Renn A. Duncan, Kristen M. Gilliland, Daniel H. Haymer, Paul K. Spearing, Rory A. Capstick, Bartholomew P. Roland, Paige Vinson, Marc Quitalig, Caroline Baggeroer, Natasha B. Billard, Jonathan W. Dickerson, Katherine J. Watson, Valerie M. Kramlinger, Olivier Boutaud, Daniel Ursu, Carsten T. Wotjak, Henning Priepke, Michel Garneau, Kristina Trenz, Colleen M. Niswender, Hyekyung P. Cho, Jerri M. Rook, Matthias Freiwald, Riccardo Giovannini, Heiko Sommer, Scott Hobson, P. Jeffrey Conn, Bruce J. Melancon, Craig W. Lindsley, Carson W. Reed
{"title":"Discovery of VU6052959/BI’7927: A Selective mGlu3 Positive Allosteric Modulator (PAM) from an Orthogonal Benzoxazine Chemotype","authors":"Caleb A. Jones, Renn A. Duncan, Kristen M. Gilliland, Daniel H. Haymer, Paul K. Spearing, Rory A. Capstick, Bartholomew P. Roland, Paige Vinson, Marc Quitalig, Caroline Baggeroer, Natasha B. Billard, Jonathan W. Dickerson, Katherine J. Watson, Valerie M. Kramlinger, Olivier Boutaud, Daniel Ursu, Carsten T. Wotjak, Henning Priepke, Michel Garneau, Kristina Trenz, Colleen M. Niswender, Hyekyung P. Cho, Jerri M. Rook, Matthias Freiwald, Riccardo Giovannini, Heiko Sommer, Scott Hobson, P. Jeffrey Conn, Bruce J. Melancon, Craig W. Lindsley, Carson W. Reed","doi":"10.1021/acsmedchemlett.6c00318","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00318","url":null,"abstract":"<p>We report the discoveryof an additional selective metabotropicglutamate receptor subtype 3 (mGlu<sub>3</sub>) positive allostericmodulator (PAM) tool compound, VU6052959/BI’7927. A high-throughputscreening (HTS) campaign identified a selective mGlu<sub>3</sub> PAMVU6046180/BI’3690 (<strong>7</strong>) containing a benzoxazinecore (an orthogonal chemotype to previously reported thiophene toolcompound VU6053371/BI’8809 (<strong>6</strong>)). Lead optimizationefforts focused on improving PK parameters led to the identificationof VU6052959/BI’7927 (<strong>8</strong>). Orthogonal PAM <strong>8</strong> demonstrated efficacy in a rat novel object recognitiontask with conservation of our previously determined PK/PD relationship.However, an Ames positive metabolite halted further progression of <strong>8</strong>.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1901–1908"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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