73279-04-6Relevant articles and documents
Utility of hepatocytes to model species differences in the metabolism of loxtidine and to predict pharmacokinetic parameters in rat, dog and man
Bayliss,Bell,Jenner,Park,Wilson
, p. 253 - 268 (1999)
1. The metabolism of loxtidine (1-methyl-5-[3-[3-[(1-piperidinyl) methyl] phenoxy] propyl] amino-1H-1,2,4-triazole-3-methanol) was studied in freshly isolated rat, dog and human hepatocytes. Metabolism in vitro was comparable with previously available in vivo data in all three species with the marked species differences observed in vivo being reproduced in the hepatocyte model. 2. The major route for the metabolism of loxtidine by rat hepatocytes was N-dealkylation to form the propionic acid and hydroxymethyl triazole metabolites. A minor metabolic route was the oxidation of loxtidine to a carboxylic acid metabolite. The major route of metabolism for loxtidine in dog hepatocytes was glucuronidation with oxidation to the carboxylic acid metabolite being of minor importance. Incubation of loxtidine with human hepatocytes resulted in the drug remaining largely unchanged but with the carboxylic acid metabolite being produced in minor amounts. 3. In vitro studies were undertaken with rat, dog and human hepatocytes to determine the Michaelis-Menten parameters V(max) and K(m) for the sum of all the metabolic pathways. These kinetic parameters were used to calculate the intrinsic clearance of loxtidine. Using appropriate scaling factors, the predicted in vivo hepatic clearance was then calculated. The predicted intrinsic clearances were 51.4 ± 12.4, 8.0 ± 0.8 and 1.0 ± 0.6 ml/min/kg for rat, dog and human hepatocytes respectively. These data were then used to calculate hepatic clearances of 24.5, 3.1 and 0.2 ml/min/kg for rat, dog and man respectively. 4. In vivo hepatic and intrinsic clearances for loxtidine were determined in rat, dog and human volunteers. The hepatic clearances of loxtidine were 26.6, 6.6 and 0.4 ml/min/kg in rat, dog and man respectively and intrinsic clearances were 58.5, 18.6 and 2.0 ml/min/kg in rat, dog and man respectively. 5. The present studies demonstrate that the hepatocyte model may be a valuable in vitro tool for predicting both qualitative and quantitative aspects of the metabolism of a drug in animals and man at an early stage of the drug development process.
Preparation method of high-purity medicinal roxatidine acetate hydrochloride
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Paragraph 0038-0041, (2021/02/06)
The invention discloses a preparation method of high-purity medicinal roxatidine acetate hydrochloride, and relates to the field of medicine synthesis. The invention provides the preparation method ofthe medicinal roxatidine acetate hydrochloride which is simple in production process, high in safety coefficient, low in cost, high in yield and extremely low in impurity content. The method comprises the following steps: 1) preparing 3-piperidine methylphenol; (2) preparing N-[3-(3-aminopropoxy)-benzyl] piperidine from the 3-piperidine methylphenol obtained in the step (1); and (3) preparing theroxatidine acetate hydrochloride by adopting the N-[3-(3-aminopropoxy)-benzyl] piperidine in the step (2). The yield of the roxatidine acetate hydrochloride prepared by the method disclosed by the invention can reach 87%, and the purity can reach 99.45%. The method is applied to the field of medicine synthesis.
High-Throughput Screening of Reductive Amination Reactions Using Desorption Electrospray Ionization Mass Spectrometry
Cooks, R. Graham,Ferreira, Christina R.,Li, Yangjie,Logsdon, David L.,Paschoal Sobreira, Tiago Jose,Thompson, David H.
supporting information, p. 1647 - 1657 (2020/10/26)
This study describes the latest generation of a high-throughput screening system that is capable of screening thousands of organic reactions in a single day. This system combines a liquid handling robot with desorption electrospray ionization (DESI) mass spectrometry (MS) for a rapid reaction mixture preparation, accelerated synthesis, and automated MS analysis. A total of 3840 unique reductive amination reactions were screened to demonstrate the throughputs that are capable with the system. Products, byproducts, and intermediates were all monitored in full-scan mass spectra, generating a complete view of the reaction progress. Tandem mass spectrometry experiments were conducted to verify the identity of the products formed. The amine and electrophile reactivity trends represented in the data match what is expected from theory, indicating that the system accurately models the reaction performance. The DESI results correlated well with those generated using more traditional mass spectrometry techniques like liquid chromatography-mass spectrometry, validating the data generated by the system.
