ArticleDrug design, development and therapy2022
Preclinical Pharmacokinetics, Tissue Distribution and in vitro Metabolism of FHND6091, a Novel Oral Proteasome Inhibitor.
Article in Drug design, development and therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 5 citations in OpenAlex.
- Identification of a New, Potent, and Stable Tetrahydroquinoline-Based 5-LOX/sEH Dual Inhibitor with Polymodal Anti-Inflammatory Activity in Acute Pancreatitis.Journal of medicinal chemistry · 2026Article
- Age (juvenile to aged) and sex effects on in vitro CYP2A6 enzyme activity in African green monkeys using nicotine and coumarin.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- 2-Phenylquinolines Exhibit Anti-Severe Acute Respiratory Syndrome Coronavirus-2 Activity Through the Nonstructural Protein 13 Helicase Inhibition.ChemMedChem · 2026Article
- Preclinical pharmacokinetic studies and prediction of human PK profiles for Deg-AZM, a clinical-stage new transgelin agonist.Frontiers in pharmacology · 2024Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Introduction: FHND6091, a novel N-capped dipeptidyl boronic acid proteasome inhibitor with promising pharmacological properties, entirely converted into active form FHND6081 under physiological conditions. The proteasome, a key component of the ubiquitin-proteasome pathway (UPP), has emerged as a validated target of multiple myeloma (MM) therapeutics. FHND6091 is a selective oral proteasome inhibitor that binds irreversibly to the β5 submit of the 20S proteasome and exerts anti-cancer roles. Methods: In this study, we investigated the metabolic stability, metabolite production, metabolic pathways and plasma protein binding (PPB) of FHND6081 along with its absorption, tissue distribution, excretion (ADME) and pharmacokinetics (PK) in animals. Results: Ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) identified a total of nine new metabolites after co-incubation with FHND6091 in hepatocytes from different species. A hypothetical CYP450-metabolic pathway including dehydrogenation, N-dealkylation plus mono-oxygenation and other was proposed. In addition, FHND6081 was highly bound to plasma proteins (>99%); nevertheless, it preferred to partition to red blood cells (B/P ratio: 4.91). The results of microsomal metabolic stability corroborated that FHND6081 was a moderate-clearance compound. In Caco-2 cell experiments, the compound displayed modest permeability suggesting that it may show limited bioavailability via oral routes. Furthermore, FHND6081 was extensively distributed in rats and the highest exposure was achieved in the stomach followed by the small intestine and adrenal gland. Pharmacokinetic studies were done by using Sprague-Dawley (SD) rats, oral absorption was fast and plasma exposure was dose-dependent and oral bioavailability were low. At the same dose, FHND6081 exposure was severalfold higher in whole blood than in plasma, which was consistent with blood cell partitioning. Moreover, only a small fraction of the parent compound was excreted via feces and urine and oxidative metabolites were detected in feces and plasma. Conclusion: The overall preclinical pharmacokinetic profile supported the selection and development of FHND6091 as a clinical candidate.
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