ChemInform Abstract: Aminophthalazinone Derivatives. Part 12. Methods for the Synthesis of Imidazo(2,1‐a)phthalazine and Pyrimido(2,1‐a)phthalazine Ring Systems. Part 2. Thermal Transformation of Acyloxyalkylaminopthalazinones.

Koermendy, K.; Ruff, F.; Koevesdi, I.

doi:10.1002/chin.198841217

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“…Our strategy began with the screening of literature compounds, known to be benzodiazepine site GABA-A ligands, and the Merck sample collection for GABA-A α2/α3 subtype selective leads. The 2,3-dihydrophthalazine-1,4-dione 5 (Table ) was identified as a weakly active α2/α3 binding selective compound, but initial optimization studies involving independent deletion and replacement of hydrogen-bonding and hydrophobic groups gave only inactive compounds. We were intrigued by the similarity of 5 to the known GABA-A ligand 6 (Table ), which has been reported to show some dissociation of anxiolysis and sedation, and thus, we identified the molecule 7 as one potential target along with other hybrid molecules.…”

Section: Lead Identificationmentioning

confidence: 99%

3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

et al. 2004

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Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha 1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i): alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 = 0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha 5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.

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Section: Lead Identificationmentioning

confidence: 99%

3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

et al. 2004

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ChemInform Abstract: Aminophthalazinone Derivatives. Part 12. Methods for the Synthesis of Imidazo(2,1‐a)phthalazine and Pyrimido(2,1‐a)phthalazine Ring Systems. Part 2. Thermal Transformation of Acyloxyalkylaminopthalazinones.

Abstract: O‐acetyl derivatives of the phthalazinones (I) and (VII) undergo proton‐catalyzed ring‐closure reactions in the melt to give the title ring systems (III) and (VIII), respectively.

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3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

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