6ngw › Citations

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)

Cited: 8 times
EuropePMC logo PMID: 30802056

Abstract

Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the p Ka of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency ( Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.

Articles citing this publication (8)

  1. 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)
  2. Antioxidant Activity, Molecular Docking, Quantum Studies and In Vivo Antinociceptive Activity of Sulfonamides Derived From Carvacrol. de Oliveira AS, Llanes LC, Nunes RJ, Nucci-Martins C, de Souza AS, Palomino-Salcedo DL, Dávila-Rodríguez MJ, Ferreira LLG, Santos ARS, Andricopulo AD. Front Pharmacol 12 788850 (2021)
  3. 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)
  4. S-Ethyl-Isothiocitrullin-Based Dipeptides and 1,2,4-Oxadiazole Pseudo-Dipeptides: Solid Phase Synthesis and Evaluation as NO Synthase Inhibitors. Mauchauffée E, Leroy J, Chamcham J, Ejjoummany A, Maurel M, Nauton L, Ramassamy B, Mezghenna K, Boucher JL, Lajoix AD, Hernandez JF. Molecules 28 5085 (2023)
  5. Elucidation of Pharmacological Mechanism Underlying the Anti-Alzheimer's Disease Effects of Evodia rutaecarpa and Discovery of Novel Lead Molecules: An In Silico Study. Zhang L, Xu J, Guo J, Wang Y, Wang Q. Molecules 28 5846 (2023)
  6. Influence of green tea on alcohol aggravated neurodegeneration of cortex, cerebellum and hippocampus of STZ-induced diabetic rats. Kodidela S, Shaik FB, Mittameedi CM, Mugudeeswaran S. Heliyon 9 e17385 (2023)
  7. 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)
  8. Interference of pH buffer with Pb2+-peripheral domain interactions: obstacle or opportunity? Katti S, Igumenova TI. Metallomics 12 164-172 (2020)


Quick links