73279-04-6Relevant academic research and scientific papers
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.
A preparation method for rosacea acetate hydrochloride
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Paragraph 0105; 0107-0108, (2021/12/07)
The present invention relates to the field of pharmaceutical preparation technology, in particular to a method for preparing rosatidine acetate hydrochloride. The present invention adopts m-hydroxybenzoic acid as a starting material, a wide range of sources, inexpensive, and it can be prepared by oxidation of m-hydroxytoluene, without involving a toxicity warning structure and nitrosamine impurities; at the same time, in this preparation process only involves a genotoxic warning structure substance, reducing the risk of medication of subsequent drugs.
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.
An integrated approach toward nanobret tracers for analysis of gpcr ligand engagement
Boursier, Michelle E.,Hall, Mary P.,Hurst, Robin,Killoran, Michael P.,Kirkland, Thomas A.,Levin, Sergiy,Machleidt, Thomas,Ohana, Rachel Friedman,Zimmerman, Kristopher
supporting information, (2021/05/31)
Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.
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.
Hexacyclododecylamines with sigma-1 receptor affinity and calcium channel modulating ability
Joubert, Jacques,Strydom, Natasha,Geldenhuys, Werner J.,Greyling, Yolande,Dyk, Sandra V.,Malan, Sarel F.
, p. 29 - 39 (2019/05/24)
Recent research points to the Sigma Receptor (σR) as a possible neuromodulatory system with multi-functional action and σ1Rs have been suggested as a drug target for a number of CNS conditions. Hexacyclododecylamines have shown σ1R activity and provide an advantageous scaffold for drug design that can improve the blood-brain barrier permeability of privileged structures. A series of oxa-and aza-hexaxcyclododecylamines were synthesised and evaluated for sigma-1 receptor activity and voltage-gated calcium channel blocking ability to determine the effect of inclusion of amine containing heterocycles. The compounds had promising σ1R activities (Ki = 0.067 – 11.86 μM) with the aza-hexacyclododecylamines 12, 24 and 27 showing some of the highest affinities (Ki = 0.067 μM, 0.215 μM and 0.496 μM respectively). This confirms, as observed in previous studies, that the aza compounds are more favourable for σ1R binding than their oxa counterparts. The addition of the amine heterocycle showed affinities similar to that of related structures with only two lipophilic binding regions. This indicates that the inclusion of an amine heterocycle into these structures is a viable option in the design of new σ1R ligands. Significant voltage-gated calcium channel blocking ability was also observed for 12, 24 and 27, suggesting a link between σ1R activity and intracellular calcium levels.
Novel preparation method of intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride
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, (2018/04/02)
The invention relates to a preparation method of an intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride. M-nitrobenzaldehyde is taken as the primary raw material; under the effect of a phase transfer catalyst, m- nitrobenzaldehyde is reduced by metal borohydride to obtain corresponding benzyl alcohol; in the presence of an alkali, benzyl alcohol reacts with organic sulfonyl chloride to generate active organic sulfonate; then in the presence of an alkali, organic sulfonate carries out N-alkylation reactions with piperidine to generate N-substituted piperidine derivatives; reducing the nitro groups of N-substituted piperidine derivatives to obtain corresponding amino compounds; and subjecting the amino compounds to diazotization, hydrolysis, and alkalizationin a sulfuric acid water solution to obtain 3-(1-piperidine methyl)phenol. The problem that the supply of the conventional raw material (m-hydroxyl benzaldehyde) is not enough and the cost is greatlyincreased is solved. The method is simple and safe, the raw materials are cheap and easily available, the reaction yield is high, and the method is very suitable for industrial production of 3-(1-piperidine methyl)phenol.
Preparation method of roxatidine acetate hydrochloride
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Paragraph 0009, (2017/07/20)
The invention discloses a preparation method of roxatidine acetate hydrochloride. The preparation method is characterized by adopting m-hydroxybenzaldehyde and piperidine as raw materials for carrying out chemical synthesis under the conditions of microwave radiation and high frequency ultrasonic wave, so that the product yield is improved, the reaction time is shortened, the cost is reduced, the product purity is improved, the total impurities are reduced, and an ideal effect is achieved.
Method for synthesizing Roxatidine intermediate 3-(1-piperidinyl methyl) phenol
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Paragraph 0009; 0015; 0018, (2017/04/25)
The invention discloses a method for synthesizing Roxatidine intermediate 3-(1-piperidinyl methyl) phenol and relates to the technical field of organic synthesis. M-anisyl alcohol which is cheap and easy to obtain is used as a raw material and firstly reacts with sulfinyl chloride to produce m-methoxybenzyl chloride, then the m-methoxybenzyl chloride reacts with piperidine to produce 3-(1-piperidinyl methyl) anisole, and finally demethoxylation is performed in hydrobromic acid to obtain the target product 3-(1-piperidinyl methyl) phenol. The route is clear, the yield is high, the amount of produced waste water, gas and residues is small, the recycling of solvent can be realized, the preparation cost is reduced and the cost is less than half of the cost of the original route.
Nitric oxide-releasing hypoglycemic compound, preparation method thereof, and use thereof
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Paragraph 0049-0052, (2017/03/17)
The invention belongs to the technical field of hypoglycemic drugs and provides a nitric oxide donor compound with the general formula I and a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are defined as in the specifications. The invention also relates to a preparation of the compound and discloses a medicine composition using the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and purpose thereof in the preparation of hypoglycemic drugs.
