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Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.

Xue F, Li H, Delker SL, Fang J, Martásek P, Roman LJ, Poulos TL, Silverman RB
J Am Chem Soc 132 14229-38 (2010)
Related entries: 3nlt, 3nlu, 3nlv, 3nlw, 3nlx, 3nly, 3nm0

Cited: 28 times
EuropePMC logo PMID: 20843082

Abstract

In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.

Articles - 3nlz mentioned but not cited (1)

  1. Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. Xue F, Li H, Delker SL, Fang J, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Am Chem Soc 132 14229-14238 (2010)


Reviews citing this publication (2)

  1. Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Mukherjee P, Cinelli MA, Kang S, Silverman RB. Chem Soc Rev 43 6814-6838 (2014)
  2. Recent advances toward improving the bioavailability of neuronal nitric oxide synthase inhibitors. Huang H, Silverman RB. Curr Top Med Chem 13 803-812 (2013)

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  1. Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes. Pollock J, Borkin D, Lund G, Purohit T, Dyguda-Kazimierowicz E, Grembecka J, Cierpicki T. J Med Chem 58 7465-7474 (2015)
  2. The anti-cancer agent SU4312 unexpectedly protects against MPP(+) -induced neurotoxicity via selective and direct inhibition of neuronal NOS. Cui W, Zhang Z, Li W, Hu S, Mak S, Zhang H, Han R, Yuan S, Li S, Sa F, Xu D, Lin Z, Zuo Z, Rong J, Ma ED, Choi TC, Lee SM, Han Y. Br J Pharmacol 168 1201-1214 (2013)
  3. Palladium-Catalyzed Arylation of Fluoroalkylamines. Brusoe AT, Hartwig JF. J Am Chem Soc 137 8460-8468 (2015)
  4. Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1-Bromo-1,1-difluoroalkanes. Xiao YL, Min QQ, Xu C, Wang RW, Zhang X. Angew Chem Int Ed Engl 55 5837-5841 (2016)
  5. Structural basis for isoform-selective inhibition in nitric oxide synthase. Poulos TL, Li H. Acc Chem Res 46 390-398 (2013)
  6. Intramolecular hydrogen bonding: a potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase. Labby KJ, Xue F, Kraus JM, Ji H, Mataka J, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. Bioorg Med Chem 20 2435-2443 (2012)
  7. On the selectivity of neuronal NOS inhibitors. Pigott B, Bartus K, Garthwaite J. Br J Pharmacol 168 1255-1265 (2013)
  8. Bulky Diamine Ligand Promotes Cross-Coupling of Difluoroalkyl Bromides by Iron Catalysis. An L, Xiao YL, Zhang S, Zhang X. Angew Chem Int Ed Engl 57 6921-6925 (2018)
  9. Pd-catalyzed gem-difluoroallylation of arylboronic acids with γ,γ-difluoroallylic acetates. Zhang B, Zhang X. Chem Commun (Camb) 52 1238-1241 (2016)
  10. Selective monocationic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations. Huang H, Ji H, Li H, Jing Q, Labby KJ, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Am Chem Soc 134 11559-11572 (2012)
  11. Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. Li H, Xue F, Kraus JM, Ji H, Labby KJ, Mataka J, Delker SL, Martásek P, Roman LJ, Poulos TL, Silverman RB. Bioorg Med Chem 21 1333-1343 (2013)
  12. Intraprotein electron transfer between the FMN and heme domains in endothelial nitric oxide synthase holoenzyme. Feng C, Taiakina V, Ghosh DK, Guillemette JG, Tollin G. Biochim Biophys Acta 1814 1997-2002 (2011)
  13. Rh-catalyzed intramolecular sp2 C-H bond difluoromethylenation. Li Y, Zhu J, Xie H, Li S, Peng D, Li Z, Wu Y, Gong Y. Chem Commun (Camb) 48 3136-3138 (2012)
  14. Role of an isoform-specific serine residue in FMN-heme electron transfer in inducible nitric oxide synthase. Li W, Fan W, Chen L, Elmore BO, Piazza M, Guillemette JG, Feng C. J Biol Inorg Chem 17 675-685 (2012)
  15. Improved synthesis of chiral pyrrolidine inhibitors and their binding properties to neuronal nitric oxide synthase. Xue F, Kraus JM, Labby KJ, Ji H, Mataka J, Xia G, Li H, Delker SL, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 54 6399-6403 (2011)
  16. Insights into the structural determinants for selective inhibition of nitric oxide synthase isoforms. Oliveira BL, Moreira IS, Fernandes PA, Ramos MJ, Santos I, Correia JD. J Mol Model 19 1537-1551 (2013)
  17. Nonconventional difluoroalkylation of C(sp2)-H bonds through hydroarylation. Zhu C, Song S, Zhou L, Wang DX, Feng C, Loh TP. Chem Commun (Camb) 53 9482-9485 (2017)
  18. Selective single C-F bond arylation of trifluoromethylalkene derivatives. Tang L, Liu ZY, She W, Feng C. Chem Sci 10 8701-8705 (2019)
  19. 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)
  20. The discovery of potentially selective human neuronal nitric oxide synthase (nNOS) Inhibitors: a combination of pharmacophore modelling, CoMFA, virtual screening and molecular docking studies. Xu G, Chen Y, Shen K, Wang X, Li F, He Y. Int J Mol Sci 15 8553-8569 (2014)
  21. Acid-Facilitated Debenzylation of N-Boc, N-Benzyl Double Protected 2-Aminopyridinomethylpyrrolidine Derivatives. Ji H, Jing Q, Huang J, Silverman RB. Tetrahedron 68 1359-1366 (2012)
  22. Controlling the Cleavage of Carbon-Carbon Bonds To Generate α,α-Difluorobenzyl Carbanions for the Construction of Difluoromethylbenzenes. Khatri HR, Han C, Luong E, Pan X, Adam AT, Alshammari MD, Shao Y, Colby DA. J Org Chem 84 11665-11675 (2019)
  23. 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)
  24. Decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt: a facile method for generation of difluoroenolate. Tarui A, Oduti M, Shinya S, Sato K, Omote M. RSC Adv 8 20568-20575 (2018)
  25. Investigations on the role of π-π interactions and π-π networks in eNOS and nNOS proteins. Vaideeswaran S, Ramaiah S. Bioorg Chem 49 16-23 (2013)


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