Ishtiyaque Ahmad

Indole-3-piperazinyl derivatives: Novel chemical class of 5-HT6 receptor antagonists

N(1)-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT(6) receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT(6) receptor. The compound 7a (K(i) = 3.4 nM, functional assay IC(50) = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter.

SUVN-G1031, a novel selective H3 receptor antagonist in animal models of cognitive deficits

26 of them completed the study. Electrocardiogram (ECG) records werereceived at the baseline and at the each dose of rivastigmine patch therapy (5cm2, and 10 cm2 respectively), and also blood pressure was measured baseline. Results: We studied 15 male and 11 female elderly subjects (mean age 78.2 6 7.6) with newlydiagnosed LOAD. Mean 6 SD valuesof heart rates are 72 6 15, 666 10, and 67 6 10,PR intervals are 171 6 224, 1786 21,and 1726 28, QRS durations are 886 17, 926 14 and 896 15, QT intervals are 393 6 41,411 6 31 and 408 6 33, and QTc intervals are 421 6 17, 426 6 12 and 426 6 21 (at baseline,5 cm, and 10 cm, respectively). Over two four-week each dose of rivastigmine treatment periods, there were no significant change in all ECG parameters when compared with baseline ECG parameters (Figure, table). Conclusions: According to these results, it is clear that the usual dosage of rivastigmine patch seems to be safe for elderly patients. Nevertheless,it is recommended that these patients are closely monitored for electrocardiographic changes during therapy.

SUVN-91121: A novel and selective H3 antagonist for the improvement of memory related disorders

Background: Preclinical studies have demonstrated synergistic actions of a combination of nutrients, leading to increased formation of synaptic membrane, reduced Abeta production, and improved memory. Based on these findings, a multi-nutrient composition known as Fortasyn Connect was designed for AD patients. Recently, the medical food ‘Souvenaid ’ containing Fortasyn Connect was tested in a randomized double-blind controlled clinical trial and was shown to improve memory in drug-naive mild AD patients. The results of this trial suggest a potential role for Souvenaid in AD disease management. Current standard practice in the medical management of AD involves the use of acetylcholinesterase (AChE) inhibitors, which have been reported to induce common adverse events including digestive, cardiovascular, and urogenital effects (e.g. Dronfield, 2000; Haug, 2005; Inglis, 2002; McLaren, 2003). The present study in aged rats was designed to see whether the medical food Souvenaid may be used safely in concordance with AChE inhibitors, i.e. without increasing possible side effects. Methods: Groups of 24months-old rats were fed either a diet containing Fortasyn Connect or a Control diet throughout the experiment and were administered increasing doses of an AChE-inhibitor (0 6.0 mg/kg per day for 7 days). Brain AChE activity was measured in addition to physiological parameters reported to be influenced by AChE inhibitors, such as body temperature, heart rate, micturition and locomotor activity. Results: Administration of AChE inhibitor resulted in a clear dose-dependent reduction of brain AChE-activity, as described in previous studies. In addition, the AChE inhibitor dose-dependently reduced body temperature and locomotor activity, while it increased micturition. The Fortasyn Connect diet did not have a negative effect on brain AChE activity or on any of the other physiological parameters studied. Conclusions: This study, in an aged rat model, showing the absence of interaction between the Fortasyn Connect diet and an AChE inhibitor on an extensive set of cholinergic read-out parameters, provides a good starting point to evaluate the potential benefits of Souvenaid in mild-to-moderate AD patients that receive standard pharmacological treatment in a long-term clinical setting. Currently, Souvenaid is being tested in such an add-on setting, the S-Connect study (NTR1683). Souvenaid is a registered trademark of N.V. Nutricia. Fortasyn is a trademark of N.V. Nutricia.