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Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.

Mukherjee P, Li H, Sevrioukova I, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB
J Med Chem 58 1067-88 (2015)
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Cited: 13 times
EuropePMC logo PMID: 25489882

Abstract

Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.

Articles - 4d30 mentioned but not cited (1)

  1. Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. Mukherjee P, Li H, Sevrioukova I, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 58 1067-1088 (2015)


Reviews citing this publication (2)

  1. Nitric oxide synthase and structure-based inhibitor design. Poulos TL, Li H. Nitric Oxide 63 68-77 (2017)
  2. The latest advances in the discovery of nitric oxide hybrid drug compounds. Serafim RAM, Pernichelle FG, Ferreira EI. Expert Opin Drug Discov 12 941-953 (2017)

Articles citing this publication (10)

  1. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. Kang S, Li H, Tang W, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 58 5548-5560 (2015)
  2. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 58 8694-8712 (2015)
  3. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin. Nieto CI, Cabildo MP, Cornago MP, Sanz D, Claramunt RM, Torralba MC, Torres MR, Elguero J, García JA, López A, Acuña-Castroviejo D. Molecules 20 15643-15665 (2015)
  4. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 59 4913-4925 (2016)
  5. Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. Pensa AV, Cinelli MA, Li H, Chreifi G, Mukherjee P, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 60 7146-7165 (2017)
  6. Synthesis and evaluation of antitumor activity of new 4-substituted thieno[3,2-d]pyrimidine and thienotriazolopyrimidine derivatives. Hafez HN, El-Gazzar ABA. Acta Pharm 67 527-542 (2017)
  7. 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors. Vasu D, Li H, Hardy CD, Poulos TL, Silverman RB. Bioorg Med Chem 69 116878 (2022)
  8. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 63 4528-4554 (2020)
  9. Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB. J. Med. Chem. 60 9360-9375 (2017)
  10. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Dong J, Li D, Kang L, Luo C, Wang J. Biophys Rep 9 159-175 (2023)


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