Selective Neuronal Nitric Oxide Synthase Inhibitors

Ji, Haitao; Erdal, Erik P.; Litzinger, E.A.; Seo, Jiwon; Zhu, Yaoqiu; Xue, Fengtian; Fang, Jianguo; Huang, Jinwen; Silverman, Richard B.

doi:10.2174/978160805207310904010842

Cited by 4 publications

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“…In the past two decades, a large number of nNOS inhibitors have been reported. [6–9,9] However, none of these compounds has been approved for medical use. Recently, we reported a family of syn -3,4-substituted pyrrolidine inhibitors (e.g., 1 – 3 , Figure 1) that were discovered using structure-based drug design.…”

Section: Introductionmentioning

confidence: 99%

Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

Labby

Xue

Kraus

et al. 2012

Bioorganic & Medicinal Chemistry

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Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.

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Section: Introductionmentioning

confidence: 99%

Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

Labby

Xue

Kraus

et al. 2012

Bioorganic & Medicinal Chemistry

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“…Inhibition of nNOS is a potential treatment for neurodegeneration; − however, it is challenging to make a selective inhibitor of nNOS over eNOS and iNOS in order to prevent side effects, such as hypertension, and not to interfere with normal immunological functions. The high similarity of NOS isozymes, particularly the heme active site structure, is the reason that most of the reported inhibitors provide limited isozyme selectivity, − even though those molecules bind at the active site and afford excellent potency. While some highly selective nNOS inhibitors have been successfully developed in our group, the integration of easy synthesis, bioavailability, and selectivity remains a challenge.…”

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confidence: 99%

Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors

Jing

Roman

et al. 2013

ACS Med. Chem. Lett.

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The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily-synthesized compounds containing either one (20a,b) or two (9a–d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor 9c is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either 9a or 9c show a double-headed binding mode, where each 2-aminopyridine head group interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of 9c contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of 9a to the heme propionate allows the inhibitor to adopt two different binding orientations. Both 9a and 9c bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.

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“…There is high homology among these isozymes from different species. 5 b The ratio of K i (eNOS or iNOS) to K i (nNOS). c The K i (nNOS) for inhibitor 1b is different from that previously reported because of the use of a new high throughput assay improving both speed and reproducibility. …”

Section: Figurementioning

confidence: 99%

“…1–5 As part of our research program directed toward developing novel nNOS inhibitors, we recently disclosed a series of gem -difluorinated monocationic inhibitors including compounds 1a and 1b , which are potent and highly selective inhibitors of nNOS. 6,7 Moreover, according to the results of detailed pharmacokinetic studies, 7,8 compound 1b has demonstrated intriguing cell membrane permeability and oral bioavailability, which makes it a promising drug candidate for neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Improved Synthesis of Chiral Pyrrolidine Inhibitors and Their Binding Properties to Neuronal Nitric Oxide Synthase

Xue¹,

Kraus²,

Labby³

et al. 2011

J. Med. Chem.

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We report an efficient synthetic route to chiral pyrrolidine inhibitors of neuronal nitric oxide synthase (nNOS) and crystal structures of the inhibitors bound to nNOS and to endothelial NOS. The new route enables versatile structure activity relationship studies on the pyrrolidine-based scaffold, which can be beneficial for further development of nNOS inhibitors. The X-ray crystal structures of three new fluorine-containing inhibitors bound to nNOS provide insights into the effect of the fluorine atoms on binding.

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Selective Neuronal Nitric Oxide Synthase Inhibitors

Cited by 4 publications

References 0 publications

Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors

Improved Synthesis of Chiral Pyrrolidine Inhibitors and Their Binding Properties to Neuronal Nitric Oxide Synthase

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