DC371739: A Novel Lipid-Lowering Drug Candidate Identified with Lipidomics

Unveiling DC371739: A Promising Candidate for Lipid Management Identified Through Lipidomics

We are very pleased to share the lipid-lowering new drugs study published in Cell Metabolism Journal. The authors of 'Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial' (DOI: 10.1016/j.cmet.2022.03.006) utilized MetwareBio's proprietary lipidomics detection and reported 1366 lipids. The purpose of this study is to evaluate the potential lipid-lowering effects of the small molecule DC371739. The research focuses on analyzing the lipid-lowering effects of DC371739 in vitro and in vivo, and validates its tolerability and efficacy in lipid-lowering through a Phase I clinical trial. Additionally, the study explores the mechanism of action of DC371739.

DC371739's Efficacy in Lowering Cholesterol and Triglycerides: Supported by Lipidomics Analysis

The compound DC371739, identified through screening of a small-molecule library, demonstrates potent lipid-lowering effects both in laboratory cell cultures and in live animal models. Utilizing lipidomics, the compound's efficacy in managing lipid disorders is further elucidated. In experiments with hyperlipidemic hamsters and rhesus monkeys, DC371739 significantly reduces levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), as highlighted by lipidomic analysis. Remarkably, it achieves these effects with minimal impact on liver function markers, indicating its potential as a therapeutic agent. Additionally, DC371739 exhibits low toxicity, as evidenced by no significant changes in body weight or liver enzyme levels. These findings underscore the promising role of lipidomics in characterizing DC371739 and its potential for managing lipid disorders.

Safe and Well-Tolerated: Phase I Clinical Trial Results of DC371739

DC371739, selected as a drug candidate for hypercholesterolemia treatment, underwent Phase Ib/IIa clinical trials (ClinicalTrials.gov, NCT04927221). The trials demonstrated its good safety, tolerability, and pharmacokinetic profiles at various doses. Pharmacokinetic analysis showed dose-dependent increases in the area under the curve (AUC), with a half-life (t1/2) of approximately 22-26 hours and peak times (Tmax) around 5.5-6.5 hours. No dose-limiting toxicities were observed up to 40 mg once daily for 28 days. In terms of efficacy, after 28 days of treatment with 40 mg/day, DC371739 significantly lowered serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and apolipoprotein B (ApoB) levels compared to the placebo group, with minimal changes in high-density lipoprotein cholesterol (HDL-C) levels.

DC371739's Unique Mechanism of Action: Targeting PCSK9 and ANGPTL3

The study indicates that the mechanism of action of DC371739 differs from currently known small molecule lipid-lowering drugs. DC371739 disrupts the transcription of two key genes, PCSK9 and ANGPTL3, by directly binding to the transcription factor HNF-1α. Therefore, DC371739 has the potential to simultaneously inhibit the transcription of PCSK9 and ANGPTL3, making it a highly promising candidate for lipid-lowering therapy.

A Potential Adjunct to Statin Therapy for Enhanced Lipid Control

In addition, given its distinct mechanism of action from statin drugs, DC371739 can be used in combination with statins. Rat experiments demonstrate that the combination of DC371739 with atorvastatin produces a more significant lipid-lowering effect. This finding provides a potential alternative treatment option for statin-intolerant patients.

In summary, this study successfully developed DC371739 as an efficient small molecule compound for lipid-lowering, with a mechanism of action distinct from known lipid-lowering drugs. The research reveals that targeting HNF-1a could be a potential strategy for treating hypercholesterolemia, highlighting the crucial role of lipidomics in identifying novel therapeutic targets. Additionally, the researchers speculate that DC371739 could be used as a monotherapy for high lipid levels or in combination with drugs like atorvastatin, particularly suitable for patients insensitive or intolerant to statin drugs. This study provides new insights and possibilities for future treatments of hypercholesterolemia.

Revolutionize Your Drug Development with Powerful Lipidomics Analysis

Unleash the power of lipidomics in drug discovery with MetwareBio's advanced service. Our high-throughput analysis identifies and quantifies over 4,000 lipids, providing unparalleled depth and precision. We offer unmatched specificity for 51 lipid classes and ensure reproducible results through rigorous quality control. Partner with MetwareBio's lipidomics expertise to gain deeper insights into drug-lipid interactions, uncover novel targets, and optimize drug development. Contact us today to discuss your specific research needs and explore how our expertise can elevate your success.