ArticleClinical pharmacology in drug development2023
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).
Article in Clinical pharmacology in drug development, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 63 citations in OpenAlex.
- First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.Clinical and translational science · 2024Trial
- Innate immunity: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- Advances in pharmacotherapy for fibrotic interstitial lung disease.Medical review (2021) · 2026Review
- Deconstructing the Master Switch: Advances in Direct NLRP3 Inhibition.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Neuroimmune Regulation of NLRP3 Signalling in Parkinson's Disease.Molecular neurobiology · 2026Review
- Mechanistic Characterization of a Small Molecule as a Direct NLRP3 Inhibitor via Binding to the NACHT Domain.Journal of medicinal chemistry · 2025Article
- Nrf2-Keap1 Pathway and NLRP3 Inflammasome in Parkinson's Disease: Mechanistic Crosstalk and Therapeutic Implications.Molecular neurobiology · 2025Review
- Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as anRSC medicinal chemistry · 2025Article
- Dehydrocostus Lactone Effectively Alleviates Inflammatory Diseases by Covalently and Irreversibly Targeting NLRP3.MedComm · 2025Article
- Discovery of AZD4144, a Selective and Potent NLRP3 Inhibitor for the Treatment of Inflammatory Diseases.Journal of medicinal chemistry · 2025Article
- Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.Fluids and barriers of the CNS · 2025Article
- Targeting the NLRP3 inflammasome for inflammatory disease therapy.Trends in pharmacological sciences · 2025Review
- Research Progress in the Molecular Mechanism of NLRP3 Inflammasome in Alzheimer's Disease and Regulation by Natural Plant Products.Molecular neurobiology · 2025Review
- NLRP3 Inflammasome in Vascular Dementia: Regulatory Mechanisms, Functions, and Therapeutic Implications: A Comprehensive Review.CNS neuroscience & therapeutics · 2025Review
- Paradigm Shift in Inflammatory Bowel Disease Management: Precision Medicine, Artificial Intelligence, and Emerging Therapies.Journal of clinical medicine · 2025Review
- Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome: From action mechanism to therapeutic target in clinical trials.World journal of gastrointestinal oncology · 2025Article
- NLRP3 inflammasome and pyroptosis: implications in inflammation and multisystem disorders.PeerJ · 2025Review
- Dapansutrile in multidisciplinary therapeutic applications: mechanisms and clinical perspectives.Frontiers in pharmacology · 2025Review
- Inflammasome components as new therapeutic targets in inflammatory disease.Nature reviews. Immunology · 2025Review
- Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies.Frontiers in transplantation · 2025Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1β inhibition in all dose groups for both studies. Inhibition in IL-1β and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1β and IL-18 level support its development for the management of inflammatory disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.