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Discovery of triazines as selective PDE4B versus PDE4D inhibitors.

Hagen TJ, Mo X, Burgin AB, Fox D, Zhang Z, Gurney ME
Bioorg Med Chem Lett 24 4031-4 (2014)
Cited: 23 times
EuropePMC logo PMID: 24998378

Abstract

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.

Reviews - 4nw7 mentioned but not cited (1)

  1. Guidelines for the successful generation of protein-ligand complex crystals. Müller I. Acta Crystallogr D Struct Biol 73 79-92 (2017)

Articles - 4nw7 mentioned but not cited (2)

  1. Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Hagen TJ, Mo X, Burgin AB, Fox D, Zhang Z, Gurney ME. Bioorg Med Chem Lett 24 4031-4034 (2014)
  2. Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors. Gaurav A, Gautam V. Iran J Pharm Res 16 910-923 (2017)


Reviews citing this publication (5)

  1. Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond. Baillie GS, Tejeda GS, Kelly MP. Nat Rev Drug Discov 18 770-796 (2019)
  2. PDE4B as a microglia target to reduce neuroinflammation. Pearse DD, Hughes ZA. Glia 64 1698-1709 (2016)
  3. Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer's Disease. Dhakal S, Kushairi N, Phan CW, Adhikari B, Sabaratnam V, Macreadie I. Int J Mol Sci 20 E5090 (2019)
  4. PDE4 subtypes in cancer. Hsien Lai S, Zervoudakis G, Chou J, Gurney ME, Quesnelle KM. Oncogene 39 3791-3802 (2020)
  5. Cardiac cAMP: production, hydrolysis, modulation and detection. Boularan C, Gales C. Front Pharmacol 6 203 (2015)

Articles citing this publication (15)

  1. Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders. Gurney ME, Nugent RA, Mo X, Sindac JA, Hagen TJ, Fox D, O'Donnell JM, Zhang C, Xu Y, Zhang HT, Groppi VE, Bailie M, White RE, Romero DL, Vellekoop AS, Walker JR, Surman MD, Zhu L, Campbell RF. J Med Chem 62 4884-4901 (2019)
  2. Identification of a multifunctional docking site on the catalytic unit of phosphodiesterase-4 (PDE4) that is utilised by multiple interaction partners. Houslay KF, Christian F, MacLeod R, Adams DR, Houslay MD, Baillie GS. Biochem J 474 597-609 (2017)
  3. Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities. Olsen CM, Liu QS. Front Biol (Beijing) 11 376-386 (2016)
  4. Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. Wilson NM, Gurney ME, Dietrich WD, Atkins CM. PLoS One 12 e0178013 (2017)
  5. PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice. McDonough W, Aragon IV, Rich J, Murphy JM, Abou Saleh L, Boyd A, Koloteva A, Richter W. FASEB J 34 12533-12548 (2020)
  6. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. Tripuraneni NS, Azam MA. J Biomol Struct Dyn 34 2481-2492 (2016)
  7. New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies. Guariento S, Bruno O, Fossa P, Cichero E. Mol Divers 20 77-92 (2016)
  8. Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains. Jimenez Chavez CL, Bryant CD, Munn-Chernoff MA, Szumlinski KK. Int J Mol Sci 22 5443 (2021)
  9. PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7. Huang Z, Liu J, Yang J, Yan Y, Yang C, He X, Huang R, Tan M, Wu D, Yan J, Shen B. Front Cell Dev Biol 9 783050 (2021)
  10. Pyridazinone derivatives as potential anti-inflammatory agents: synthesis and biological evaluation as PDE4 inhibitors. Allart-Simon I, Moniot A, Bisi N, Ponce-Vargas M, Audonnet S, Laronze-Cochard M, Sapi J, Hénon E, Velard F, Gérard S. RSC Med Chem 12 584-592 (2021)
  11. Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice. Boyd A, Aragon IV, Rich J, McDonough W, Oditt M, Irelan D, Fiedler E, Abou Saleh L, Richter W. Biology (Basel) 10 1355 (2021)
  12. Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor. Al-Nema M, Gaurav A, Lee VS. Heliyon 6 e04856 (2020)
  13. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. Tripuraneni NS, Azam MA. J Theor Biol 394 117-126 (2016)
  14. Selective Inhibition of PDE4B Reduces Methamphetamine Reinforcement in Two C57BL/6 Substrains. Honeywell KM, Doren EV, Szumlinski KK. Int J Mol Sci 23 4872 (2022)
  15. An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands. Jiang M, Lu S, Telu S, Pike VW. J Med Chem 66 1543-1561 (2023)


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