{"title":"Novel 3-Cycloaminoindole Compounds as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.4c0061510.1021/acsmedchemlett.4c00615","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00615https://doi.org/10.1021/acsmedchemlett.4c00615","url":null,"abstract":"<p >Provided herein are novel 3-cycloaminoindole compounds as serotonergic psychedelic agents, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"190–191 190–191"},"PeriodicalIF":3.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394152","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}
Elena Lucarini, Vanessa D’Antongiovanni, Luca Antonioli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marta Ferraroni, Maria Locuoco, Antonella Capperucci, Damiano Tanini*, Andrea Angeli* and Claudiu T Supuran,
{"title":"Correction to “Study of Chalcogen Aspirin Derivatives with Carbonic Anhydrase Inhibitory Properties for Treating Inflammatory Pain”","authors":"Elena Lucarini, Vanessa D’Antongiovanni, Luca Antonioli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marta Ferraroni, Maria Locuoco, Antonella Capperucci, Damiano Tanini*, Andrea Angeli* and Claudiu T Supuran, ","doi":"10.1021/acsmedchemlett.4c0061710.1021/acsmedchemlett.4c00617","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00617https://doi.org/10.1021/acsmedchemlett.4c00617","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"347 347"},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394274","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}
Brock E. Lynde, Danielle M. Chemaly, Vanessa Pietrowski Baldin, Eric Greve, Christopher L. Harding, Jasmin M. Graner, Mason Hardy, Sultan Chowdhury and Tanya Parish*,
{"title":"Novel 3-Aminothieno[2,3-b]pyridine-2-carboxamides with Activity against Mycobacterium tuberculosis","authors":"Brock E. Lynde, Danielle M. Chemaly, Vanessa Pietrowski Baldin, Eric Greve, Christopher L. Harding, Jasmin M. Graner, Mason Hardy, Sultan Chowdhury and Tanya Parish*, ","doi":"10.1021/acsmedchemlett.4c0047210.1021/acsmedchemlett.4c00472","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00472https://doi.org/10.1021/acsmedchemlett.4c00472","url":null,"abstract":"<p >We conducted an exploration of the 3-aminothieno[2,3-<i>b</i>]pyridine-2-carboxamide (TPA) series for its potential as a drug scaffold against <i>Mycobacterium tuberculosis</i>. Existing analogs were active against a recombinant strain of <i>M. tuberculosis</i> with reduced expression of the sole signal peptidase LepB, but with poor activity against the wild-type strain. Our aim was to improve potency and explore the structure–activity relationship of the series. We identified two subsets of TPA. The first subset of compounds had equipotent activity against wild-type and LepB hypomorph strains and may represent a series with a different target. The second subset of compounds had increased activity against the LepB hypomorph strain and thus appears to be pathway-specific. Among this latter set we identified <b>17af</b> as a potent inhibitor (IC<sub>90</sub> = 1.2 μM) with some cytotoxicity (IC<sub>50</sub> = 19 μM) and which retained increased activity against the LepB hypomorph (IC<sub>90</sub> = 0.41 μM).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"241–249 241–249"},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00472","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena Lucarini, Vanessa D'Antongiovanni, Luca Antonioli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marta Ferraroni, Maria Locuoco, Antonella Capperucci, Damiano Tanini, Andrea Angeli, Claudiu T Supuran
{"title":"Correction to \"Study of Chalcogen Aspirin Derivatives with Carbonic Anhydrase Inhibitory Properties for Treating Inflammatory Pain\".","authors":"Elena Lucarini, Vanessa D'Antongiovanni, Luca Antonioli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marta Ferraroni, Maria Locuoco, Antonella Capperucci, Damiano Tanini, Andrea Angeli, Claudiu T Supuran","doi":"10.1021/acsmedchemlett.4c00617","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00617","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1021/acsmedchemlett.4c00284.].</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"347"},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brock E Lynde, Danielle M Chemaly, Vanessa Pietrowski Baldin, Eric Greve, Christopher L Harding, Jasmin M Graner, Mason Hardy, Sultan Chowdhury, Tanya Parish
{"title":"Novel 3-Aminothieno[2,3-<i>b</i>]pyridine-2-carboxamides with Activity against <i>Mycobacterium tuberculosis</i>.","authors":"Brock E Lynde, Danielle M Chemaly, Vanessa Pietrowski Baldin, Eric Greve, Christopher L Harding, Jasmin M Graner, Mason Hardy, Sultan Chowdhury, Tanya Parish","doi":"10.1021/acsmedchemlett.4c00472","DOIUrl":"10.1021/acsmedchemlett.4c00472","url":null,"abstract":"<p><p>We conducted an exploration of the 3-aminothieno[2,3-<i>b</i>]pyridine-2-carboxamide (TPA) series for its potential as a drug scaffold against <i>Mycobacterium tuberculosis</i>. Existing analogs were active against a recombinant strain of <i>M. tuberculosis</i> with reduced expression of the sole signal peptidase LepB, but with poor activity against the wild-type strain. Our aim was to improve potency and explore the structure-activity relationship of the series. We identified two subsets of TPA. The first subset of compounds had equipotent activity against wild-type and LepB hypomorph strains and may represent a series with a different target. The second subset of compounds had increased activity against the LepB hypomorph strain and thus appears to be pathway-specific. Among this latter set we identified <b>17af</b> as a potent inhibitor (IC<sub>90</sub> = 1.2 μM) with some cytotoxicity (IC<sub>50</sub> = 19 μM) and which retained increased activity against the LepB hypomorph (IC<sub>90</sub> = 0.41 μM).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"241-249"},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Callum A Rosser, Samuel V Feeney, Lukas Roth, David E Hibbs, Michael P Gotsbacher, Rachel Codd
{"title":"Carboxamide-Bearing Panobinostat Analogues Designed To Interact with E103-D104 at the Cavity Opening of Class I HDAC Isoforms.","authors":"Callum A Rosser, Samuel V Feeney, Lukas Roth, David E Hibbs, Michael P Gotsbacher, Rachel Codd","doi":"10.1021/acsmedchemlett.4c00494","DOIUrl":"10.1021/acsmedchemlett.4c00494","url":null,"abstract":"<p><p>Panobinostat (<b>1</b>) inhibits Zn(II)-dependent histone deacetylases (HDACs) which are validated cancer targets. Three sets of <b>1</b> analogues containing carboxamide groups designed to form hydrogen bonds with acidic residues (E103, D104) in the cavity opening of a subset of class I isoforms were synthesized and evaluated against HDAC2. All <b>1</b> analogues (IC<sub>50</sub> range: 150-3320 nM) were less potent HDAC2 inhibitors than <b>1</b> (IC<sub>50</sub> = 5 nM). Ensemble docking showed that the carboxamide NH<sub>2</sub> group in the most potent <b>1</b> analogues <i>S</i>-<b>3</b> (IC<sub>50</sub> = 150 nM) and <i>S</i>-<b>2</b> (IC<sub>50</sub> = 350 nM) enabled hydrogen bond formation with E103 and D104. The proximity of the electron withdrawing carboxamide to the secondary amine in the <b>1</b> analogues reduced calculated p<i>K</i> <sub>a</sub> values, compared to <b>1</b>. Reduced electrostatic binding capacity of the <b>1</b> analogues, together with solvation and steric penalties, was proposed to negate the binding energy benefit of increased hydrogen bonding. Ensemble docking suggested isoform selectivity as unlikely.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"250-257"},"PeriodicalIF":3.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Callum A. Rosser, Samuel V. Feeney, Lukas Roth, David E. Hibbs, Michael P. Gotsbacher* and Rachel Codd*,
{"title":"Carboxamide-Bearing Panobinostat Analogues Designed To Interact with E103-D104 at the Cavity Opening of Class I HDAC Isoforms","authors":"Callum A. Rosser, Samuel V. Feeney, Lukas Roth, David E. Hibbs, Michael P. Gotsbacher* and Rachel Codd*, ","doi":"10.1021/acsmedchemlett.4c0049410.1021/acsmedchemlett.4c00494","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00494https://doi.org/10.1021/acsmedchemlett.4c00494","url":null,"abstract":"<p >Panobinostat (<b>1</b>) inhibits Zn(II)-dependent histone deacetylases (HDACs) which are validated cancer targets. Three sets of <b>1</b> analogues containing carboxamide groups designed to form hydrogen bonds with acidic residues (E103, D104) in the cavity opening of a subset of class I isoforms were synthesized and evaluated against HDAC2. All <b>1</b> analogues (IC<sub>50</sub> range: 150–3320 nM) were less potent HDAC2 inhibitors than <b>1</b> (IC<sub>50</sub> = 5 nM). Ensemble docking showed that the carboxamide NH<sub>2</sub> group in the most potent <b>1</b> analogues <i>S</i>-<b>3</b> (IC<sub>50</sub> = 150 nM) and <i>S</i>-<b>2</b> (IC<sub>50</sub> = 350 nM) enabled hydrogen bond formation with E103 and D104. The proximity of the electron withdrawing carboxamide to the secondary amine in the <b>1</b> analogues reduced calculated p<i>K</i><sub>a</sub> values, compared to <b>1</b>. Reduced electrostatic binding capacity of the <b>1</b> analogues, together with solvation and steric penalties, was proposed to negate the binding energy benefit of increased hydrogen bonding. Ensemble docking suggested isoform selectivity as unlikely.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"250–257 250–257"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397356","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}
Bruno D Chapsal, Jennifer R Kimbrough, Stephanie M Bester, Alex Bergstrom, Donald S Backos, Bismarck Campos, Matthew G McDonald, Rebecca Abrahamsen, Andrew C Allen, Patrick M Doerner Barbour, Tanna Bettendorf, Mark L Boys, Karin Brown, Mark J Chicarelli, Adam W Cook, Amy L Crooks, Cole L Cruz, Joshua R Dahlke, Alida Eide, Jay B Fell, Jennifer L Fulton, Matthew Gargus, John J Gaudino, Anna L Guarnieri, Erik P Hansen, Melissa C Holt, Dean R Kahn, Ellen R Laird, Paul D Larsen, Rebecca Linwood, Matthew C Martinson, Joseph McCown, Macedonio J Mejia, David A Moreno, Tung-Chung Mou, Brad Newhouse, Jacob M O'Leary, Martha E Rodriguez, Anurag Singh, Lenka Sinik, Keith A Strand, Eric E Touney, Lance A Wollenberg, Jim Wong, Yeyun Zhou, John P Fischer, Shelley Allen
{"title":"Design of Potent Menin-KMT2A Interaction Inhibitors with Improved <i>In Vitro</i> ADME Properties and Reduced hERG Affinity.","authors":"Bruno D Chapsal, Jennifer R Kimbrough, Stephanie M Bester, Alex Bergstrom, Donald S Backos, Bismarck Campos, Matthew G McDonald, Rebecca Abrahamsen, Andrew C Allen, Patrick M Doerner Barbour, Tanna Bettendorf, Mark L Boys, Karin Brown, Mark J Chicarelli, Adam W Cook, Amy L Crooks, Cole L Cruz, Joshua R Dahlke, Alida Eide, Jay B Fell, Jennifer L Fulton, Matthew Gargus, John J Gaudino, Anna L Guarnieri, Erik P Hansen, Melissa C Holt, Dean R Kahn, Ellen R Laird, Paul D Larsen, Rebecca Linwood, Matthew C Martinson, Joseph McCown, Macedonio J Mejia, David A Moreno, Tung-Chung Mou, Brad Newhouse, Jacob M O'Leary, Martha E Rodriguez, Anurag Singh, Lenka Sinik, Keith A Strand, Eric E Touney, Lance A Wollenberg, Jim Wong, Yeyun Zhou, John P Fischer, Shelley Allen","doi":"10.1021/acsmedchemlett.4c00311","DOIUrl":"10.1021/acsmedchemlett.4c00311","url":null,"abstract":"<p><p>Inhibitors of the interaction of menin (MEN1) with lysine methyltransferase 2A (KMT2A) have emerged as novel therapeutic options in the treatment of genetically defined acute leukemias. Herein, we describe the structure-based design, synthesis, and biological evaluation of novel inhibitors of the menin-KMT2A interaction. Our structure-activity relationship campaign focused on achieving high antiproliferative cellular activity while mitigating risks associated with CYP3A4-dependent metabolism and hERG inhibition, which were characterized in some early clinical candidates. Our efforts resulted in the discovery of a triazine-based compound series that inhibited MV4-11 leukemia cell line proliferation with IC<sub>50</sub> as low as 13 nM, and selected compounds demonstrated improved <i>in vitro</i> ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"224-233"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruno D. Chapsal*, Jennifer R. Kimbrough, Stephanie M. Bester, Alex Bergstrom, Donald S. Backos, Bismarck Campos, Matthew G. McDonald, Rebecca Abrahamsen, Andrew C. Allen, Patrick M. Doerner Barbour, Tanna Bettendorf, Mark L. Boys, Karin Brown, Mark J. Chicarelli, Adam W. Cook, Amy L. Crooks, Cole L. Cruz, Joshua R. Dahlke, Alida Eide, Jay B. Fell, Jennifer L. Fulton, Matthew Gargus, John J. Gaudino, Anna L. Guarnieri, Erik P. Hansen, Melissa C. Holt, Dean R. Kahn, Ellen R. Laird, Paul D. Larsen, Rebecca Linwood, Matthew C. Martinson, Joseph McCown, Macedonio J. Mejia, David A. Moreno, Tung-Chung Mou, Brad Newhouse, Jacob M. O’Leary, Martha E. Rodriguez, Anurag Singh, Lenka Sinik, Keith A. Strand, Eric E. Touney, Lance A. Wollenberg, Jim Wong, Yeyun Zhou, John P. Fischer and Shelley Allen,
{"title":"Design of Potent Menin–KMT2A Interaction Inhibitors with Improved In Vitro ADME Properties and Reduced hERG Affinity","authors":"Bruno D. Chapsal*, Jennifer R. Kimbrough, Stephanie M. Bester, Alex Bergstrom, Donald S. Backos, Bismarck Campos, Matthew G. McDonald, Rebecca Abrahamsen, Andrew C. Allen, Patrick M. Doerner Barbour, Tanna Bettendorf, Mark L. Boys, Karin Brown, Mark J. Chicarelli, Adam W. Cook, Amy L. Crooks, Cole L. Cruz, Joshua R. Dahlke, Alida Eide, Jay B. Fell, Jennifer L. Fulton, Matthew Gargus, John J. Gaudino, Anna L. Guarnieri, Erik P. Hansen, Melissa C. Holt, Dean R. Kahn, Ellen R. Laird, Paul D. Larsen, Rebecca Linwood, Matthew C. Martinson, Joseph McCown, Macedonio J. Mejia, David A. Moreno, Tung-Chung Mou, Brad Newhouse, Jacob M. O’Leary, Martha E. Rodriguez, Anurag Singh, Lenka Sinik, Keith A. Strand, Eric E. Touney, Lance A. Wollenberg, Jim Wong, Yeyun Zhou, John P. Fischer and Shelley Allen, ","doi":"10.1021/acsmedchemlett.4c0031110.1021/acsmedchemlett.4c00311","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00311https://doi.org/10.1021/acsmedchemlett.4c00311","url":null,"abstract":"<p >Inhibitors of the interaction of menin (MEN1) with lysine methyltransferase 2A (KMT2A) have emerged as novel therapeutic options in the treatment of genetically defined acute leukemias. Herein, we describe the structure-based design, synthesis, and biological evaluation of novel inhibitors of the menin–KMT2A interaction. Our structure–activity relationship campaign focused on achieving high antiproliferative cellular activity while mitigating risks associated with CYP3A4-dependent metabolism and hERG inhibition, which were characterized in some early clinical candidates. Our efforts resulted in the discovery of a triazine-based compound series that inhibited MV4-11 leukemia cell line proliferation with IC<sub>50</sub> as low as 13 nM, and selected compounds demonstrated improved <i>in vitro</i> ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"224–233 224–233"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397251","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":"Discovery of a Phosphodiesterase 7A Inhibitor of High Isozyme Selectivity Exhibiting <i>In Vivo</i> Anti-Osteoporotic Effects.","authors":"Kentaro Kondo, Kazuki Otake, Tetsudo Kaya, Shohei Miwa, Yoshifumi Ueyama, Tsunemitsu Haruta, Jun Nishihata, Takashi Nakagawa, Nobuhide Azuma, Kayoko Takagi, Toshiki Urashima, Yuki Kitao, Makoto Shiozaki","doi":"10.1021/acsmedchemlett.4c00570","DOIUrl":"10.1021/acsmedchemlett.4c00570","url":null,"abstract":"<p><p>Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor <b>26</b>. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the <i>in vivo</i> antiosteoporotic effects.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 1","pages":"167-173"},"PeriodicalIF":3.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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