215874-89-8Relevant academic research and scientific papers
TRIAZOLO-PYRIDAZINE COMPOUNDS AND DERIVATIVES THEREOF USEFUL IN THE TREATMENT OF NEUROPATHIC PAIN
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Page/Page column 56, (2010/02/11)
The present invention is directed to a method of use of triazolo-pyridazine compounds in the treatment of neuropathic pain. The present invention is also directed to the use of triazolo-pyridazine compounds in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson’s disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders - such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases. The present invention is also directed to novel triazolo-pyridazine compounds that selectively bind to α2δ-1 subunit of Ca channels.
Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro- (7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABAAα5 benzodiazepine binding site
Street, Leslie J.,Sternfeld, Francine,Jelley, Richard A.,Reeve, Austin J.,Carling, Robert W.,Moore, Kevin W.,McKernan, Ruth M.,Sohal, Bindi,Cook, Susan,Pike, Andrew,Dawson, Gerard R.,Bromidge, Frances A.,Wafford, Keith A.,Seabrook, Guy R.,Thompson, Sally A.,Marshall, George,Pillai, Goplan V.,Castro, José L.,Atack, John R.,MacLeod, Angus M.
, p. 3642 - 3657 (2007/10/03)
The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)- 1,2,4-triazolo[3,4-a]phthalazines as GABAAα5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of α5- over α1-, α2-, and α3-containing GABAA receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABAAα5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4- triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABAAα5 subtype with functional selectivity over the other GABAA receptor subtypes and good oral bioavailability.
Selective, Orally Active γ-Aminobutyric AcidA α5 Receptor Inverse Agonists as Cognition Enhancers
Sternfeld, Francine,Carling, Robert W.,Jelley, Richard A.,Ladduwahetty, Tamara,Merchant, Kevin J.,Moore, Kevin W.,Reeve, Austin J.,Street, Leslie J.,O'Connor, Desmond,Sohal, Bindi,Atack, John R.,Cook, Susan,Seabrook, Guy,Wafford, Keith,Tattersall, F. David,Collinson, Neil,Dawson, Gerard R.,Castro, José L.,MacLeod, Angus M.
, p. 2176 - 2179 (2007/10/03)
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.
Identification and synthesis of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to the α2δ -1 subunit of voltage gated calcium channel
Lebsack, Alec D.,Gunzner, Janet,Wang, Bowei,Pracitto, Richard,Schaffhauser, Herve,Santini, Angelina,Aiyar, Jayashree,Bezverkov, Robert,Munoz, Benito,Liu, Wensheng,Venkatraman, Shankar
, p. 2463 - 2467 (2007/10/03)
We have identified and synthesized a series of [1,2,4]triazolo[3,4-a] phthalazine derivatives as high-affinity ligands to α2δ-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC50=15nM) and (S)-22 (IC50=30nM). A potent and selective radioligand, [3H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.
