- Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase
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The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.
- Breen, C. J.,Devine, R.,Driver, R. B.,Findlay, J. B. C.,Kelada, M.,Kinsella, G. K.,Leonard, S.,Martin, D. S. D.,Stephens, J. C.,Walsh, J. M. D.
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- N-ACYL-N'-PHENYLPIPERAZINE DERIVATIVES AS SRBP MODULATORS FOR USE IN THE TREATMENT OF DIABETES AND OBESITY
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The present invention relates to compounds having the general formula (I) as described herein; methods of preparing said compounds; and their use in treating Type 1 and/or Type 2 Diabetes Mellitus. The compounds were assayed for binding to serum retinol binding protein (sRBP) and for disruption of the sRBP:transthyretin (TTR) and sRBP:sRBP receptor interaction. The compounds were also assayed for their ability to induce glucose uptake into mouse muscle cells. Also described is a pharmaceutical composition comprising a compound according to the first aspect of the present invention, and use thereof in treating Type 1 and Type 2 Diabetes.
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(2013/05/21)
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