In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Abstract

Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: . For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests.

Robust and Fast UV–HPLC Method for Biotransformation Analysis of Azecines

“…Due to the high structural homology of azecines, it is very likely possible to adapt this method to other derivatives as well. In addition, LE404 occurs as postulated intermediate at most of the azecines [12]. The proposed method requires analytical devices that are standard equipment in most laboratories, involves a low effort in sample preparation and allows the analytical procedure to be performed within a relatively short time.…”

“…This also promotes a consistently good separation even in semi-preparative conditions. The phosphate buffer of the mobile phase used here can be removed by extraction after the semi-preparative separation, because LE404, with a octanol/water-partition coefficient (log P O/W ) of 3.33 [12], can be extracted very good by organic solvents. Thus, the use of buffer substances in the mobile phase is not an exclusion criterion for a semipreparative separation.…”

“…In addition, the fivefold higher therapeutic range of LE404, compared to the standard substances haloperidol and risperidone, characterizes the azecines as potentially useful drugs against schizophrenia [9]. In further research, LE404 prodrugs with altered pharmacokinetic properties were synthesized [10,11] and screened in in vivo and in vitro assays [12]. However, there is no information about the metabolism of azecines at this time.…”

HPLC–UV Monitored Photostability-Test of LE404 and Identification of the Degradation Products via NMR and LC–HRMS

“…The azecines are a promising new class of API for the treatment of schizophrenia. After the synthesis of prodrugs [9], the in vitro and in vivo testing for e cacy and side effects [8], the studies of stability in physiological media [10] and beginning investigations on biotransformation [15]. The next signi cant research focus is the photo-and oxidative degradation studies conducted in this article.…”

“…In addition to that, LE404 has a 5-fold higher therapeutic range than the standard substances [7]. In further research, many LE404 prodrugs with altered pharmacokinetic properties were synthesized [8,9] and showed consistently very good neuroleptic potency in vivo and in vitro [10]. Due to the selective binding to the D 1 receptor subtype (D 1 , D 5 ) and the simultaneous binding to the 5-HT 2A receptor, side effects can be kept to a minimum [5,7].…”