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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 5548-60 (2015)
Related entries: 4ugz, 4uh0, 4uh1, 4uh2, 4uh3, 4uh4, 4uh6, 4uh7, 4uh8, 4uh9, 4uha

Cited: 17 times
EuropePMC logo PMID: 26120733

Abstract

We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

Articles - 4uh5 mentioned but not cited (3)

  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. Antioxidant-Rich Woodfordia fruticosa Leaf Extract Alleviates Depressive-Like Behaviors and Impede Hyperglycemia. Tayab MA, Chowdhury KAA, Jabed M, Mohammed Tareq S, Kamal ATMM, Islam MN, Uddin AMK, Hossain MA, Emran TB, Simal-Gandara J. Plants (Basel) 10 287 (2021)
  3. 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)


Reviews citing this publication (1)

  1. Nitric oxide synthase and structure-based inhibitor design. Poulos TL, Li H. Nitric Oxide 63 68-77 (2017)

Articles citing this publication (13)

  1. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 60 3958-3978 (2017)
  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. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 62 2690-2707 (2019)
  4. Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase. Li H, Wang HY, Kang S, Silverman RB, Poulos TL. Biochemistry 55 3702-3707 (2016)
  5. 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)
  6. 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)
  7. 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)
  8. A catalyst- and solvent-free thermal multicomponent approach for the construction of diverse and polysubstituted 2-aminopyridines and their antibacterial activity. Baral ER, Sharma K, Akhtar MS, Lee YR. Org Biomol Chem 14 10285-10297 (2016)
  9. Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors. Vasu D, Do HT, Li H, Hardy CD, Awasthi A, Poulos TL, Silverman RB. J Med Chem 66 9934-9953 (2023)
  10. Three-Component Cascade Reaction of 1,1-Enediamines, N,N-Dimethylformamide Dimethyl Acetal, and 1,3-Dicarbonyl Compounds: Selective Synthesis of Diverse 2-Aminopyridine Derivatives. Zi QX, Yan SJ, Yang CL, Li K, Lin J. ACS Omega 4 2863-2873 (2019)
  11. Crystallographic and Computational Insights into Isoform-Selective Dynamics in Nitric Oxide Synthase. Li H, Hardy CD, Reidl CT, Jing Q, Xue F, Cinelli M, Silverman RB, Poulos TL. Biochemistry 63 788-796 (2024)
  12. Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies. Kibou Z, Aissaoui N, Daoud I, Seijas JA, Vázquez-Tato MP, Klouche Khelil N, Choukchou-Braham N. Molecules 27 3439 (2022)
  13. 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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