Remote protection prevents unwanted cyclizations with 2-aminopyridines

Lawton, Graham R.; Ji, Haitao; Silverman, Richard B.

doi:10.1016/j.tetlet.2006.06.091

Cited by 16 publications

(10 citation statements)

References 9 publications

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“…So 44 or 48a was oxidized to a ketone, and then reductive amination was carried out to generate the trans amines, as shown in Schemes 1 and 2 22,23. Later, we discovered that Mitsunobu reactions proceeded smoothly when the mono Boc protected 2-amino group of the 2-aminopyridine moiety of 44 was further protected with a benzyl group or an additional Boc group 30. In this study we continued to use a benzyl group as the protecting group to protect 48a , which allowed the S N 2 reaction to proceed, and to synthesize the trans isomers, as shown in Scheme 3.…”

Section: Resultsmentioning

confidence: 99%

Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

Delker

et al. 2010

J. Med. Chem.

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Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8–34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors [(±)-32 and (±)-34] with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3′-[2″-(3‴-fluorophenethylamino)ethoxy]pyrrolidin-4′-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3′R, 4′R)-4 can induce enzyme elasticity to generate a new “hot spot” for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3′R, 4′R)-3′-[2″-(3‴-fluorophenethylamino)ethylamino]pyrrolidin-4′-yl}methyl}-4-methylpyridin-2-amine ((3′R, 4′R)-3) (J. Am. Chem. Soc. 2010, 132(15), 5437–5442). On the basis of structure-activity relationships of 8–34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

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Section: Resultsmentioning

confidence: 99%

Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

Delker

et al. 2010

J. Med. Chem.

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“…The disadvantage of these synthetic routes is that both the cis and trans isomers are generated, although they can be effectively separated by silica gel column chromatography. Later, we discovered that the Mitsunobu reaction can proceed smoothly when the Boc protected 2-amino group of the 2-aminopyridine moiety of 35 is further protected with a benzyl group 34. In this study, we continued to use a benzyl group to protect 45a to generate 61 .…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping

Martásek

et al. 2009

J. Med. Chem.

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Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity, but more drug-like properties can be achieved by fragment hopping. Based on the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better drug-like properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure-based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known drug-like small-molecule modulators are still limited.

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“…Boc-protected aminopyridine 4 was treated with 2 equiv of n -BuLi, and the resulting dianion was allowed to react with epoxide 5 13 to give secondary alcohol 6 in good yields. Next, 6 was converted to a bis-Boc-protected alcohol using a three-step procedure 27. First, the hydroxyl group was protected as the t -butyldimethylsilyl (TBS)-ether ( 7 ) using TBSCl in the presence of imidazole.…”

Section: Chemistrymentioning

confidence: 99%

Structure-based design, synthesis, and biological evaluation of lipophilic-tailed monocationic inhibitors of neuronal nitric oxide synthase

Xue¹,

Huang²,

Ji³

et al. 2010

Bioorganic & Medicinal Chemistry

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Selective inhibitors of neuronal nitric oxide synthase (nNOS) have the potential to develop into new neurodegenerative therapeutics. Recently, we described the discovery of novel nNOS inhibitors (1a and 1b) based on a cis-pyrrolidine pharmacophore. These compounds and related ones were found to have poor blood-brain barrier permeability, presumably because of the basic nitrogens in the molecule. Here, a series of monocationic compounds was designed on the basis of docking experiments using the crystal structures of 1a,b bound to nNOS. These compounds were synthesized and evaluated for their ability to inhibit neuronal nitric oxide synthase. Despite the excellent overlap of these compounds with 1a,b bound to nNOS, they exhibited low potency. This is because they bound in the nNOS active site in the normal orientation rather than the expected flipped orientation used in the computer modeling. The biphenyl or phenoxyphenyl tail is disordered and does not form good protein-ligand interactions. These studies demonstrate the importance of the size and rigidity of the side chain tail and the second basic amino group for nNOS binding efficiency and the importance of the hydrophobic tail for conformational orientation in the active site of nNOS.

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Remote protection prevents unwanted cyclizations with 2-aminopyridines

Cited by 16 publications

References 9 publications

Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping

Structure-based design, synthesis, and biological evaluation of lipophilic-tailed monocationic inhibitors of neuronal nitric oxide synthase

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