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One-Pot Synthesis of Novel Tetrasubstituted α-Aminophosphonates Derived from α-Methylphosphoserine and In Vivo Evaluation as Anti-Inflammatory Agents
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-18 DOI: 10.1021/acs.jmedchem.4c02496
Misael López-Castillo, Mario Ordóñez, Itzel Bernal-Evangelista, Gil A. Vázquez-Arredondo, Martha Vanessa Gutiérrez-Baños, Ivan Romero-Estudillo, Gabriela Castañeda-Corral
A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) “Kabachnik-Fields reaction.” The novel α-aminophosphonates were screened for in vivo anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds 2, 5, and 7 showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds 27 reduced CFA-induced paw edema, as did indomethacin or (S)-naproxen. Based on the promising in vivo anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles in silico. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski’s rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.
{"title":"One-Pot Synthesis of Novel Tetrasubstituted α-Aminophosphonates Derived from α-Methylphosphoserine and In Vivo Evaluation as Anti-Inflammatory Agents","authors":"Misael López-Castillo, Mario Ordóñez, Itzel Bernal-Evangelista, Gil A. Vázquez-Arredondo, Martha Vanessa Gutiérrez-Baños, Ivan Romero-Estudillo, Gabriela Castañeda-Corral","doi":"10.1021/acs.jmedchem.4c02496","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02496","url":null,"abstract":"A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) “Kabachnik-Fields reaction.” The novel α-aminophosphonates were screened for <i>in vivo</i> anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds <b>2</b>, <b>5,</b> and <b>7</b> showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds <b>2</b>–<b>7</b> reduced CFA-induced paw edema, as did indomethacin or (<i>S</i>)-naproxen. Based on the promising <i>in vivo</i> anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles <i>in silico</i>. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski’s rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c03106
Brian S. Gerstenberger, Ray Unwalla, Kathleen A. Farley, Philippe Nuhant, Vincent M. Lombardo, Wei Li, Kimberly Crouse, Richard K. Frisbie, Eric P. Arnold, Mark W. Bundesmann, Gary M. Chinigo, Andrew Flick, Neelu Kaila, Daniel Lamb, James J. Mousseau, Nootaree Niljianskul, Mathieu Rappas, John I. Trujillo, Michael L. Vazquez, Atli Thorarensen, Mark E. Schnute
CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6+ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the cis-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.
{"title":"Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists","authors":"Brian S. Gerstenberger, Ray Unwalla, Kathleen A. Farley, Philippe Nuhant, Vincent M. Lombardo, Wei Li, Kimberly Crouse, Richard K. Frisbie, Eric P. Arnold, Mark W. Bundesmann, Gary M. Chinigo, Andrew Flick, Neelu Kaila, Daniel Lamb, James J. Mousseau, Nootaree Niljianskul, Mathieu Rappas, John I. Trujillo, Michael L. Vazquez, Atli Thorarensen, Mark E. Schnute","doi":"10.1021/acs.jmedchem.4c03106","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03106","url":null,"abstract":"CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6<sup>+</sup> T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the <i>cis</i>-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Opening the Door to a New Treatment Paradigm: The Re-emergence of Chymase Inhibitors
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.5c00413
Franz von Nussbaum, Giambattista Testolin
Chymase is a serine protease that has been studied as a drug target in inflammatory diseases, so far with limited success. Fulacimstat is a novel drug candidate inhibiting chymase that has been investigated in clinical trials for the role of chymase in inflammation. Despite a good safety profile, further clinical development of fulacimstat was not pursued due to a lack of efficacy. Recently, a new role of chymase in blood clot biology has been identified, this resparks interest in chymase inhibitors, and positions fulacimstat as a potential innovative option to treat thrombotic conditions.
{"title":"Opening the Door to a New Treatment Paradigm: The Re-emergence of Chymase Inhibitors","authors":"Franz von Nussbaum, Giambattista Testolin","doi":"10.1021/acs.jmedchem.5c00413","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00413","url":null,"abstract":"Chymase is a serine protease that has been studied as a drug target in inflammatory diseases, so far with limited success. Fulacimstat is a novel drug candidate inhibiting chymase that has been investigated in clinical trials for the role of chymase in inflammation. Despite a good safety profile, further clinical development of fulacimstat was not pursued due to a lack of efficacy. Recently, a new role of chymase in blood clot biology has been identified, this resparks interest in chymase inhibitors, and positions fulacimstat as a potential innovative option to treat thrombotic conditions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02199
Shuting Xu, Kaiqi Long, Tianyi Wang, Yangyang Zhu, Yunjiao Zhang, Weiping Wang
Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.
{"title":"Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition","authors":"Shuting Xu, Kaiqi Long, Tianyi Wang, Yangyang Zhu, Yunjiao Zhang, Weiping Wang","doi":"10.1021/acs.jmedchem.4c02199","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02199","url":null,"abstract":"Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02897
Gebhard Thoma, Wolfgang Miltz, Rudolf Waelchli, David Orain, Carsten Spanka, Odile Decoret, Romain M. Wolf, Brian Hurley, Atwood K. Cheung, David A. Sandham, Ayako Honda, Ritesh Tichkule, Xin Chen, Tajesh Patel, Nancy Labbe-Giguere, Kian L. Tan, Clayton Springer, John Manchester, Andrew J. Culshaw, Peter Hunt, Honnappa Srinivas, Carlos A. Penno, Sandrine Ferrand, Shin Numao, Ulrich Schopfer, Petra Jäger, Nathalie Wack, Franziska Hasler, Beatrice Urban, Miriam Sindelar, Pius Loetscher, Michael Kiffe, Xiaojun Ren, Paul Nicklin, Kevin White, Khaushik Subramanian, Haoyuan Liu, Ellena J. Growcott, Till A. Röhn
Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.
{"title":"Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase","authors":"Gebhard Thoma, Wolfgang Miltz, Rudolf Waelchli, David Orain, Carsten Spanka, Odile Decoret, Romain M. Wolf, Brian Hurley, Atwood K. Cheung, David A. Sandham, Ayako Honda, Ritesh Tichkule, Xin Chen, Tajesh Patel, Nancy Labbe-Giguere, Kian L. Tan, Clayton Springer, John Manchester, Andrew J. Culshaw, Peter Hunt, Honnappa Srinivas, Carlos A. Penno, Sandrine Ferrand, Shin Numao, Ulrich Schopfer, Petra Jäger, Nathalie Wack, Franziska Hasler, Beatrice Urban, Miriam Sindelar, Pius Loetscher, Michael Kiffe, Xiaojun Ren, Paul Nicklin, Kevin White, Khaushik Subramanian, Haoyuan Liu, Ellena J. Growcott, Till A. Röhn","doi":"10.1021/acs.jmedchem.4c02897","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02897","url":null,"abstract":"Leukotriene C4 synthase (LTC4S) is a glutathione <i>S</i>-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound <b>1</b>), which exhibits 20-fold improved potency (IC<sub>50</sub> = 44 nM) versus clinical candidate AZD9898 (IC<sub>50</sub> = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration
IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c0275110.1021/acs.jmedchem.4c02751
François P. Bischoff*, Sven Van Brandt, Marcel Viellevoye, Michel De Cleyn, Michel Surkyn, Rodrigo J. Carbajo, Maria Dominguez Blanco, Berthold Wroblowski, Nathan K. Karpowich, Ruth A. Steele, Celine Schalk-Hihi, Robyn Miller, David Duda, Paul Shaffer, Scott Ballentine, Sirak Simavorian, Brian Lord, Robert A. Neff, Pascal Bonaventure and Harrie J. M. Gijsen*, 

N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

{"title":"Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration","authors":"François P. Bischoff*,&nbsp;Sven Van Brandt,&nbsp;Marcel Viellevoye,&nbsp;Michel De Cleyn,&nbsp;Michel Surkyn,&nbsp;Rodrigo J. Carbajo,&nbsp;Maria Dominguez Blanco,&nbsp;Berthold Wroblowski,&nbsp;Nathan K. Karpowich,&nbsp;Ruth A. Steele,&nbsp;Celine Schalk-Hihi,&nbsp;Robyn Miller,&nbsp;David Duda,&nbsp;Paul Shaffer,&nbsp;Scott Ballentine,&nbsp;Sirak Simavorian,&nbsp;Brian Lord,&nbsp;Robert A. Neff,&nbsp;Pascal Bonaventure and Harrie J. M. Gijsen*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0275110.1021/acs.jmedchem.4c02751","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02751https://doi.org/10.1021/acs.jmedchem.4c02751","url":null,"abstract":"<p ><i>N</i>-Methyl-<span>d</span>-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The <b>TCN-201</b> derivatives <b>MPX-004</b> and <b>MPX-007</b> are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the <b>MPX-004</b>/<b>MPX-007</b> scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound <b>1</b> was used to develop the first GluN2A NAM-based radioligand, and compound <b>11</b> showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 4","pages":"4672–4693 4672–4693"},"PeriodicalIF":6.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists
IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c0310610.1021/acs.jmedchem.4c03106
Brian S. Gerstenberger, Ray Unwalla, Kathleen A. Farley, Philippe Nuhant, Vincent M. Lombardo, Wei Li, Kimberly Crouse, Richard K. Frisbie, Eric P. Arnold, Mark W. Bundesmann, Gary M. Chinigo, Andrew Flick, Neelu Kaila, Daniel Lamb, James J. Mousseau, Nootaree Niljianskul, Mathieu Rappas, John I. Trujillo, Michael L. Vazquez, Atli Thorarensen and Mark E. Schnute*, 

CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6+ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the cis-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.

{"title":"Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists","authors":"Brian S. Gerstenberger,&nbsp;Ray Unwalla,&nbsp;Kathleen A. Farley,&nbsp;Philippe Nuhant,&nbsp;Vincent M. Lombardo,&nbsp;Wei Li,&nbsp;Kimberly Crouse,&nbsp;Richard K. Frisbie,&nbsp;Eric P. Arnold,&nbsp;Mark W. Bundesmann,&nbsp;Gary M. Chinigo,&nbsp;Andrew Flick,&nbsp;Neelu Kaila,&nbsp;Daniel Lamb,&nbsp;James J. Mousseau,&nbsp;Nootaree Niljianskul,&nbsp;Mathieu Rappas,&nbsp;John I. Trujillo,&nbsp;Michael L. Vazquez,&nbsp;Atli Thorarensen and Mark E. Schnute*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0310610.1021/acs.jmedchem.4c03106","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03106https://doi.org/10.1021/acs.jmedchem.4c03106","url":null,"abstract":"<p >CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6<sup>+</sup> T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the <i>cis</i>-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 4","pages":"4818–4828 4818–4828"},"PeriodicalIF":6.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02751
François P. Bischoff, Sven Van Brandt, Marcel Viellevoye, Michel De Cleyn, Michel Surkyn, Rodrigo J. Carbajo, Maria Dominguez Blanco, Berthold Wroblowski, Nathan K. Karpowich, Ruth A. Steele, Celine Schalk-Hihi, Robyn Miller, David Duda, Paul Shaffer, Scott Ballentine, Sirak Simavorian, Brian Lord, Robert A. Neff, Pascal Bonaventure, Harrie J. M. Gijsen
N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.
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引用次数: 0
Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition
IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c0219910.1021/acs.jmedchem.4c02199
Shuting Xu, Kaiqi Long, Tianyi Wang, Yangyang Zhu, Yunjiao Zhang and Weiping Wang*, 

Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.

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引用次数: 0
Impact of Fluorine Pattern on Lipophilicity and Acid–Base Properties of 2-(Thiofluoroalkyl)pyridines: Insights from Experiments and Statistical Modeling
IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c0304510.1021/acs.jmedchem.4c03045
Miguel Bernús, Gonzalo D. Núñez, Will C. Hartley, Marc Guasch, Jordi Mestre, Maria Besora*, Jorge J. Carbó* and Omar Boutureira*, 

Lipophilicity and acid–base properties are two key aspects of the optimization of a compound in drug discovery. Using 19F NMR, we experimentally determined the log D7.4 of a wide array of 2-thiofluoroalkyl (SRF) and 2-sulfonyl fluoroalkyl (SO2RF) substituted pyridines and the pKa values of their protonated counterparts. Statistical modeling based on constitutional and DFT descriptors provided further insights into the structure–property relationship, explaining the experimental observations and predicting log D7.4 values. Our results highlight the influence of fluorination topology in SRF fragments and demonstrate the dual effect of fluorine on molecular polarity, increasing the hydrophobic surface and the polarity of the sulfur moiety. By analyzing methyl- and ethyl-derived fragments, we found a gradient in log D7.4 values influenced by the oxidation state of the sulfur atom and fluorination pattern. Our findings emphasize the context-dependent impact of fluorination and offer insights to better understand the impact of thiofluoroalkyl chains on these physicochemical properties.

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引用次数: 0
期刊
Journal of Medicinal Chemistry
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