IN VITRO METABOLISM OF THE CALMODULIN ANTAGONIST DY-9760e (3-[2-[4-(3-CHLORO-2-METHYLPHENYL)-1-PIPERAZINYL]ETHYL]-5,6-DIMETHOXY-1-(4-IMIDAZOLYLMETHYL)-1H-INDAZOLE DIHYDROCHLORIDE 3.5 HYDRATE) BY HUMAN LIVER MICROSOMES: INVOLVEMENT OF CYTOCHROMES P450 IN ATYPICAL KINETICS AND POTENTIAL DRUG INTERACTIONS

Abstract

DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (Fig. 1), is a novel calmodulin antagonist being developed to treat acute ischemic stroke. It inhibits calmodulin-dependent enzymes and in so doing exerts neuroprotective effects in animals with induced strokes (Sugimura et al., 1997;Sato et al., 1999Sato et al., , 2003Sato et al., , 2004Fukunaga et al., 2000;Takagi et al., 2001;Hashiguchi et al., 2003). In experimental model rats with transient focal ischemia, DY-9760e significantly reduces the infarct volume when infused for 6 h from 1 h after the middle cerebral artery occlusion and also suppresses the increase in brain water content. Results of a previous study show that DY-9760e is metabolized by human liver microsomes in vitro, and the major metabolites of DY-9760e are identified as N-dealkylated (DY-9836), 4-hydroxylated (M3), O-demethylated (M5 and M7), and imidazole-oxidized derivatives (M6 and M8) ( Fig. 1; Tachibana et al., 2005b). The results of pharmacokinetic studies in rats after intravenous administration of DY-9760e show that DY9760e is extensively metabolized in the liver, and most of the administered DY-9760e is excreted into bile as glucuronide conjugates of hydroxylated and O-demethylated metabolites (Tachibana et al., 2005a,b). Therefore, DY-9760e is eliminated mainly through hepatic metabolic clearance.Although the general outline of DY-9760e metabolism is known, more specific information is needed to understand its complex metabolism. Thus, this study had two purposes. One purpose of this study was to identify which human P450 isozyme(s) are involved in the formation of the primary metabolites of DY-9760e, and to determine the enzyme kinetics for the formation of metabolites using human liver microsomes and microsomes expressing recombinant human P450 enzymes. These studies provide essential information for determining the contribution of each P450 isozyme to DY-9760e metabolism. The second purpose of the present study was to estimate how

Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

“…Therefore, the discovery of more-efficient drugs for the treatment of VaD is of great significance. We previously reported that a calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]­ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), could reduce the infarct volume, diminish blood–brain barrier (BBB) breakdown, and suppress the elevated signal intensities present in the cortical region of the ipsilateral hemisphere in T2-weighted magnetic resonance imaging (MRI) studies. , Moreover, DY-9760e was capable of reducing BBB breakdown in a brain ischemia model by inhibition of calpain activation, calcium- and calmodulin-dependent nitric synthase activation, and protein tyrosine nitration. − 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]­ethyl]-5,6-dimethoxyindazole (DY-9836), a pharmacologically active metabolite of DY-9760e, does not interfere with the metabolism of other drugs in liver; thus, it seems more attractive than DY-9760e for clinical application, with great potential for the treatment of VaD. Nevertheless, low water solubility and poor pharmakinetics of DY-9836 (DY) restrict its further application.…”

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

“…Training and test set compounds for this model are shown in Table 18. [67,[124][125][126][127][128][129][130][131][132] (S)-verapamil ((S)-19) [124], nifedipine (29) [124], astemizole (110) [107], and quinidine (166) [124] were employed as additional test set compounds. (Fig.…”