202931-56-4

Upstream product

• 613-94-5 benzoic acid hydrazide 
• 202823-67-4 3,6-dichloro-4,5-diazatricyclo[6.2.2.2,7]dodeca-2⁽⁷⁾,3,5-triene 
• 79363-47-6 3-chloro-6-hydrazino-4,5-diazatricyclo[6.2.2.2,7]dodeca-2⁽⁷⁾,3,5-triene 
• 65-85-0 benzoic acid 
• 202823-65-2 2,3,5,6,7,8-hexahydro-5,8-ethanophthalazine-1,4-dione 

Downstream Products

• 848774-97-0 3-phenyl-7,8,9,10-tetrahydro-7,10-ethano[1,2,4]triazolo[3,4-a]phthalazine-6-carbonitrile 
• 848774-98-1 3-phenyl-7,8,9,10-tetrahydro-7,10-ethano[1,2,4]triazolo[3,4-a]phthalazine-6-carboxamide 

Relevant academic research and scientific papers

Selective, Orally Active γ-Aminobutyric AcidA α5 Receptor Inverse Agonists as Cognition Enhancers

Nonselective inverse agonists at the γ-aminobutyric acidA (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A α5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.

Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazines as GABAA receptor agonists at the α3 subunit

We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the 0.3 receptor subtype with 5-fold selectivity in binding affinity over α1. This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the α3 subtype over the α1 subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at α1 and antagonism at α3 (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the α3 subtype over the α1 subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

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

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 γ-aminobutyric acid-A (GABA-A) α3- and α5-containing receptor subtypes over the GABA-A α1 subtype (Ki: α2 = 850 nM, α3 = 170 nM, α5 = 72 nM, α1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: α2 = 16 nM, α3 = 41 nM, α5 = 38 nM, α1 = 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: α2 = 1.7 nM, α3 = 0.71 nM, α5 = 0.33 nM, α1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes, 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes α1, -7%; α2, -5%; α3, -16%; α5, -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 α3 over α1 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 α3-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 α2/α3 agonist in vivo.

Substituted triazolo-pyridazine derivatives as ligands for GABA receptors

Substituted triazolo-pyridazine derivative compounds represented by wherein the variables are disclosed herein are selective ligands for GABA-A receptors, particularly for the α2 and/or α3 subunits.