Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives

Patel, Anup B.; Malpass, John R.

doi:10.1021/jm800537a

Cited by 13 publications

(7 citation statements)

References 54 publications

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“…The product is relatively unstable and can be polymerized very quickly; therefore, it should be used immediately for the next step. All analytical data are consistent with the literature …”

Section: Methodssupporting

confidence: 89%

“…The crude compound was sufficiently pure to be used directly in the next step. All analytical data are consistent with the literature …”

Section: Methodssupporting

confidence: 89%

“…The key step was an intramolecular photochemical [2 + 2]-cyclization . In 2003, Malpass repeated the synthesis of amino acid 3 and prepared conformationally restricted nicotinic acetylcholine ligands . In 2010, Varnes and colleagues from AstraZeneca also used this strategy to obtain 20 g of amino acid 3 .…”

Section: Introductionmentioning

confidence: 99%

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Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Levterov

Michurin

Borysko³

et al. 2018

J. Org. Chem.

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A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.

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“…The product is relatively unstable and can be polymerized very quickly; therefore, it should be used immediately for the next step. All analytical data are consistent with the literature …”

Section: Methodssupporting

confidence: 89%

“…The crude compound was sufficiently pure to be used directly in the next step. All analytical data are consistent with the literature …”

Section: Methodssupporting

confidence: 89%

See 1 more Smart Citation

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Levterov

Michurin

Borysko³

et al. 2018

J. Org. Chem.

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“…Reagents and conditions are as follows: (g) CH2Cl2, C2Cl2O2, DMSO, NEt3, −78°C, 2 h, [21] (h) THF, NaH, C8H17O5P, N2, 0°C, 2h,[22] (i) CH3CH2OH, LiOH, 15 h[23]. …”

Section: Resultsmentioning

confidence: 99%

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts

Han

Ruan

et al. 2016

Oncotarget

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Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are derived from the anilinoquinazoline scaffold. Guided by molecular modeling, this series of analogs was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and to achieve high levels of anti-tumor activity in cell cultures and in xenografts. The most promising compound 13c ((E) –N - (4 - (4 - (3-fluorobenzyloxy) -3- chlorophenylamino) -7-ethoxyquinazolin-6-yl) -3- ((S) -pyrrolidin-2-yl)acrylamide, which we named Transtinib) displayed strong anti-proliferative activity against the H1975 and A431 cell lines with IC50 values of 34 nM and 62 nM, respectively. In xenograft models, Transtinib significantly decreases tumor size for a prolonged period of time. These results suggest that Transtinib is a potential cancer therapeutic drug lead for the inhibition of mutant EGFR to overcome the development of resistance.

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“…However, very few analogues bearing the pyridine substituent at the bridgehead of the azabicyclo[2.2.1]heptane are present in literature. 20 This substitution pattern offers a major advantage because, in this way, chirality is stripped from the bicyclic system by a plane of symmetry (Fig. 2).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands

et al. 2014

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The highly potent natural alkaloid epibatidine remains a source of inspiration in the search for new analgesic drugs. In this paper, we describe an expansion of our previously reported synthesis of epibatidine analogues, and five synthetic alkaloids characterized by a symmetric, 1-substituted 7-azabicyclo[2.2.1]heptane skeleton, were evaluated for their biological activity. Two of these are binding selectively to the a 4 b 2 subtype of the nicotinic acetylcholine receptor. Their K i values were determined to be 40 and 290 nM.After a favourable evaluation of these compounds' cytotoxicity and metabolic stability, they were submitted to a rat tail flick test. The compounds did not show antinociceptive effects, which may be caused by a combination of insufficient potency and poor brain penetration.

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Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives

Cited by 13 publications

References 54 publications

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts

Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands

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Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives

Cited by 13 publications

References 54 publications

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts

Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α4β2 nicotinic acetylcholine receptor ligands

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Product

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Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands