81395-70-2Relevant articles and documents
LONG-ACTING LOW-ADDICTION HNK DERIVATIVE AND PREPARATION METHOD THEREFOR
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, (2022/04/06)
The present application relates to a compound having the functions of being an antidepressant, improving anxiety and post-traumatic stress syndrome, anesthetizing, easing pain, improving cognitive function, protecting the lungs, preventing or treating amyotrophic lateral sclerosis or preventing or treating complex regional pain syndrome. Compared with existing known HNK compounds, the compound of the present invention has a longer drug efficacy period, and the compound of the present invention essentially does not lead to addiction.
Enzyme-Mediated Two-Step Regio- And Stereoselective Synthesis of Potential Rapid-Acting Antidepressant (2 S,6 S)-Hydroxynorketamine
Bokel, Ansgar,Hutter, Michael C.,Rühlmann, Ansgar,Urlacher, Vlada B.
, p. 4151 - 4159 (2020/05/05)
Recently, the anesthetic (S)-ketamine has been approved as a rapid-acting and long-lasting antidepressant. Its metabolite, (2S,6S)-hydroxynorketamine, has been found to have a similar antidepressant effect but with less undesirable side effects, which make this compound an interesting target for synthesis. Using the first-sphere mutagenesis of the cytochrome P450 154E1 from Thermobifida fusca YX, we constructed a triple mutant that enables the effective production of (2S,6S)-hydroxynorketamine from (S)-ketamine. This engineered P450 monooxygenase catalyzes the consecutive oxidative N-demethylation and highly regio- and stereoselective C6-hydroxylation reactions leading directly to the desired product with 85% product selectivity. The integration of this selective monooxygenase into an Escherichia coli whole-cell biocatalyst allowed the production of (2S,6S)-hydroxynorketamine at a semipreparative scale. The metabolite was purified and its structure was confirmed by NMR spectroscopy.
Microbial biotransformation–an important tool for the study of drug metabolism
Salter, Rhys,Beshore, Douglas C.,Colletti, Steven L.,Evans, Liam,Gong, Yong,Helmy, Roy,Liu, Yong,Maciolek, Cheri M.,Martin, Gary,Pajkovic, Natasa,Phipps, Richard,Small, James,Steele, Jonathan,de Vries, Ronald,Williams, Headley,Martin, Iain J.
, p. 877 - 886 (2018/09/27)
Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies. Examples of the microbial synthesis of several difficult-to-synthesize hydroxylated metabolites and three difficult-to-synthesize glucuronidated metabolites are described, and the use of microbial biotransformation in drug discovery and development is discussed.
