Synthesis of isotopically labeled daclatasvir for use in human clinical studies

Easter, John A.; Burrell, Richard C.; Bonacorsi, Samuel J.

doi:10.1002/jlcr.3386

Cited by 3 publications

(2 citation statements)

References 14 publications

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“…The imidazole core is another ubiquitous motif present in drugs. Easter and coworkers recently reported the access to [ 14 C]‐declatasvir, an intriguing example of symmetric imidazole‐containing drug (Scheme 11).…”

Section: Introductionmentioning

confidence: 99%

Recent developments in heterocycle labeling with carbon isotopes

Vecchio

Destro

Taran

2018

Labelled Comp Radiopharmac

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Heterocycles play an essential role in modern pharmaceutical and agrochemical developments, representing a very common structural unit in marketed drugs. Over the 46 new drugs approved in 2017 by the FDA, 25 contain in their structure a heterocyclic core. The development of novel and straightforward labeling strategies for the effective insertion of carbon isotopes into heterocylic scaffolds is an inspiring and vibrant field of research. The use of carbon-11, carbon-13, and carbon-14 isotopes is well established in life science and particularly in pharmaceutical and agrochemical industry. Their introduction into small organic molecules represents a crucial step for the radiochemists. Because the labeling should occur in metabolically stable positions and in the shortest synthetic route, their incorporation into the heterocycles represents a viable solution. This review summarizes recent contributions to this area of research through the analysis of different industrial and academic cases.

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Section: Introductionmentioning

confidence: 99%

Recent developments in heterocycle labeling with carbon isotopes

Vecchio

Destro

Taran

2018

Labelled Comp Radiopharmac

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“…Here, we report the preclinical biotransformation of daclatasvir, including a full structural characterization of key metabolites. (Easter et al, 2016) (Phillipsburg, NJ). Pooled liver microsomes (male cynomolgus monkey, lot 23791, n = 150; male beagle dog, lot 00269, n = 7; male Sprague-Dawley rat, lot 85157, n = 164; male human, lot 382898, n = 150) were obtained from BD Gentest (Woburn, MA).…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine -Oxidation and Rearrangement

Zhao

Liu

et al. 2016

Drug Metabolism and Disposition

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Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included d-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.

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Dimeric Drugs

Nudelman

2022

CMC

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This review intends to summarize the structures of an extensive number of symmetrical-dimeric drugs, having two monomers linked via a bridging entity while emphasizing the large versatility of biologically active substances reported to possess dimeric structures. The largest number of classes of these compounds consist of anticancer agents, antibiotics/antimicrobials, and anti-AIDS drugs. Other symmetrical-dimeric drugs include antidiabetics, antidepressants, analgesics, anti-inflammatories, drugs for the treatment of Alzheimer’s disease, anticholesterolemics, estrogenics, antioxidants, enzyme inhibitors, anti-Parkisonians, laxatives, antiallergy compounds, cannabinoids, etc. Most of the articles reviewed do not compare the activity/potency of the dimers to that of their corresponding monomers. Only in limited cases, various suggestions have been made to justify unexpected higher activity of the dimers vs. the corresponding monomers. These suggestions include statistical effects, the presence of dimeric receptors, binding of a dimer to two receptors simultaneously, and others. It is virtually impossible to predict which dimers will be preferable to their respective monomers, or which linking bridges will lead to the most active compounds. It is expected that the extensive number of articles summarized, and the large variety of substances mentioned, which display various biological activities, should be of interest to many academic and industrial medicinal chemists.

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Synthesis of isotopically labeled daclatasvir for use in human clinical studies

Cited by 3 publications

References 14 publications

Recent developments in heterocycle labeling with carbon isotopes

Recent developments in heterocycle labeling with carbon isotopes

Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine -Oxidation and Rearrangement

Dimeric Drugs

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