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Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity.

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<div class='caption-title'>Synthesis of 3R and 3S</div>
Kang S, Tang W, Li H, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB
OpenAccess logo J Med Chem 57 4382-96 (2014)
Related entries: 4ctp, 4ctq, 4ctr, 4ctt, 4ctu, 4ctv, 4ctw, 4ctx, 4cty, 4cu0, 4cu1

Cited: 14 times
EuropePMC logo PMID: 24758147

Abstract

Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of α-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors.

Articles - 4ctz mentioned but not cited (1)

  1. Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity. Kang S, Tang W, Li H, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 57 4382-4396 (2014)


Reviews citing this publication (3)

  1. Nitric oxide synthase inhibitors: a review of patents from 2011 to the present. Yang Y, Yu T, Lian YJ, Ma R, Yang S, Cho JY. Expert Opin Ther Pat 25 49-68 (2015)
  2. Nitric oxide synthase and its function in animal reproduction: an update. Zhang W, Chen SJ, Guo LY, Zhang Z, Zhang JB, Wang XM, Meng XB, Zhang MY, Zhang KK, Chen LL, Li YW, Wen Y, Wang L, Hu JH, Bai YY, Zhang XJ. Front Physiol 14 1288669 (2023)
  3. Advancements in the Research of New Modulators of Nitric Oxide Synthases Activity. Maccallini C, Budriesi R, De Filippis B, Amoroso R. Int J Mol Sci 25 8486 (2024)

Articles citing this publication (10)



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