Search for α3β2/3γ2 subtype selective ligands that are stable on human liver microsomes
Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABAA) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties.
Namjoshi, Ojas A.,Wang, Zhi-Jian,Rallapalli, Sundari K.,Johnson Jr., Edward Merle,Johnson, Yun-Teng,Ng, Hanna,Ramerstorfer, Joachim,Varagic, Zdravko,Sieghart, Werner,Majumder, Samarpan,Roth, Bryan L.,Rowlett, James K.,Cook, James M.
p. 93 - 101
(2013/02/22)
Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects
The present invention provides compositions and methods of using stereospecific benzodiazepine derivatives, their salts and prodrugs for the treatment of anxiolytic or convulsant disorders having the side effects of reduced alcohol craving in human alcoholics and a concomitant reduced sedative, hypnotic, muscle relaxant and ataxic side-effects. The invention further provides pharmaceutical compositions for treatment of anxiolytic and convulsant disorders in subjects in need thereof, comprising a compound, prodrug or a salt having a chemical structure represented by any one of Formula I-XXI and a pharmaceutically-acceptable carrier.
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Page/Page column 37-38
(2008/06/13)
ANXIOLYTIC AGENTS WITH REDUCED SEDATIVE AND ATAXIC EFFECTS
Orally active benzodiazepine derivatives and their salts are disclosed. These compounds and their salts have anxiolytic and anticonvulsant activity with reduced sedative/hypnotic/muscle relaxant/ataxic effects.
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Page/Page column 64-65
(2010/02/07)
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