120199-64-6Relevant articles and documents
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)
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 (2019)
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.
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.
Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine
Zheng, Zhen,Kyzer, Jillian L.,Worob, Adam,Wenthur, Cody J.
, p. 4113 - 4122 (2021/11/01)
The dissociative-hypnotic compound ketamine is being used in an increasingly wide range of therapeutic contexts, including anesthesia, adjunctive analgesia, treatment-resistant depression, but it also continues to be a notable substance of abuse. No specific antidotes exist for ketamine intoxication or overdose. Immunopharmacotherapy has demonstrated the ability to offer overdose protection through production of highly specific antibodies that prevent psychoactive drug penetration across the blood-brain barrier, although antiketamine antibodies have not yet been assessed or optimized for use in this approach. Moreover, generation of specific antibodies also provides an opportunity to address the role of 6-hydroxynorketamine metabolites in ketamine's rapid-acting antidepressant effect through selective restriction of metabolite access to the central nervous system. Hapten design is a critical element for tuning immune recognition of small molecules, as it affects the presentation of the target antigen and thus the quality and selectivity of the response. Here, we report the synthesis and optimization of carrier protein and conjugation conditions for an initial hapten, norketamine-N-COOH (NK-N-COOH), to optimize vaccination conditions and assess the functional consequences of such vaccination on ketamine-induced behavioral alterations occurring at dissociative-like (50 mg/kg) doses. Iterating from this initial approach, two additional haptens, ketamine-N-COOH (KET-N-COOH) and 6-hydroxynorketamine-N-COOH (HNK-N-COOH), were synthesized to target either ketamine or 6-hydroxynorketamine with greater selectivity. The ability of these haptens to generate antiketamine, antinorketamine, and anti-6-hydroxynorketamine immune responses in mice was then assessed using enzyme-linked immunosorbent assay (ELISA) and competitive surface plasmon resonance (SPR) methods. All three haptens provoked immune responses in vivo, although the KET-N-COOH and 6-HNK-N-COOH haptens yielded antibodies with 5- to 10-fold improvements in affinity for ketamine and/or 6-hydroxynorketamine, as compared to NK-N-COOH. Regarding selectivity, vaccines bearing a KET-N-COOH hapten yielded an antibody response with approximately equivalent Kd values against ketamine (86.4 ± 3.2 nM) and 6-hydroxynorketamine (74.1 ± 7.8 nM) and a 90-fold weaker Kd against norketamine. Contrastingly, 6-HNK-N-COOH generated the highest affinity and most selective antibody profile, with a 38.3 ± 4.7 nM IC50 against 6-hydroxynorketamine; Kd values for ketamine and norketamine were 33- to 105-fold weaker, at 1290 ± 281.5 and 3971 ± 2175 nM, respectively. Overall, these findings support the use of rational hapten design to generate antibodies capable of distinguishing between structurally related, yet mechanistically distinct, compounds arising from the same precursor molecule. As applied to the production of the first-reported anti-6-hydroxynorketamine antibodies to date, this approach demonstrates a promising path forward for identifying the individual and combinatorial roles of ketamine and its metabolites in supporting rewarding effects and/or rapid-acting antidepressant activity.
CRYSTAL FORMS AND METHODS OF SYNTHESIS OF (2R, 6R)-HYDROXYNORKETAMINE AND (2S, 6S)-HYDROXYNORKETAMINE
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, (2019/02/19)
The disclosure provides a method for synthesizing free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine. In an embodiment synthesis of (2R,6R)-hydroxynorketamine (HNK) includes preparation of (R)-norketamine via chiral resolution from racemic norketamine via a chiral resolution with L-pyroglutamic acid. The disclosure also provided crystal forms of the corresponding (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine hydrochloride salts.
HYDROXYNORKETAMINE DERIVATIVES FOR THE TREATMENT OF CNS DISORDERS
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, (2018/03/25)
Chemical entities of Formula (I): Including enantiomers thereof, wherein R1 has any of the values described herein, and compositions comprising such chemical entities; their preparation; and their use in various methods, including the treatment of depression, pain, cognitive disorders, neurodegenerative disorders, and other neurological and peripheral disorders.
COMPOUNDS FOR THERAPEUTIC USE
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, (2018/03/25)
Chemical entities of Formula (I): Including enantiomers thereof, wherein R1 has any of the values described herein, and compositions comprising such chemical entities; their preparation; and their use in various methods, including the treatment of depression, pain, cognitive disorders, neurodegenerative disorders, and other neurological and peripheral disorders.
SOLID ORAL DOSAGE FORMS OF 2R,6R-HYDROXYNORKETAMINE OR DERIVATIVES THEREOF
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, (2018/01/17)
This invention relates to solid oral dosage forms of 2R,6R-hydroxynorketamine or prodrugs thereof having Formula Ib, including any pharmaceutically acceptable salt of the foregoing, for use in a therapeutic method for the treatment of a depressive disorder in a patient.
Synthesis and N-Methyl- d -aspartate (NMDA) Receptor Activity of Ketamine Metabolites
Morris, Patrick J.,Moaddel, Ruin,Zanos, Panos,Moore, Curtis E.,Gould, Todd,Zarate, Carlos A.,Thomas, Craig J.
, p. 4572 - 4575 (2017/09/11)
Ketamine is rapidly metabolized in the human body to a variety of metabolites, including the hydroxynorketamines. At least two hydroxynorketamines have significant antidepressant action in rodent models, with limited action against the N-methyl-d-aspartate (NMDA) receptor. The synthesis of 12 hydroxynorketamines and their binding affinity to the NMDA receptor is presented here.
THE USE OF (2R, 6R)-HYDROXYNORKETAMINE, (S)-DEHYDRONORKETAMINE AND OTHER STEREOISOMERIC DEHYDRO AND HYDROXYLATED METABOLITES OF (R,S)- KETAMINE IN THE TREATMENT OF DEPRESSION AND NEUROPATHIC PAIN
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Paragraph 0125; 0126, (2013/04/25)
The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain disorder (CRPS) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.
