Ervogastat（CAS:2186700-33-2)

Ervogastat (CAS 2186700-33-2, code name PF-06865571) is a world-first systemic selective DGAT2 inhibitor originally discovered by Pfizer and exclusively licensed to Madrigal Pharmaceuticals for clinical advancement, specifically developed for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) complicated with hepatic fibrosis. It fills the long-term R&D gap of targeted drugs acting on hepatic triglyceride synthesis pathway, and becomes a benchmark research API for fatty liver mechanism study and novel drug screening among global pharmaceutical manufacturers, universities and CRO laboratories. Appearing as off-white crystalline powder, its chemical scaffold is optimized via pyridine and tetrahydrofuran moiety modification to greatly improve metabolic stability and eliminate safety hazards of toxic quinone metabolites easily generated by early-generation DGAT2 candidates. Strict control over chiral impurities, related substances, heavy metals and residual solvents delivers HPLC purity over 99.5%, fully meeting raw material standards for in vitro cell assays, animal model construction, formulation pre-development and pre-IND new drug application. It features excellent batch uniformity and stable long-term storage resistance without degradation.

In terms of core pharmacological mechanism, DGAT2 serves as the rate-limiting key enzyme for hepatocyte triglyceride synthesis, catalyzing the conversion of diacylglycerol into triglyceride and acting as the core pathway for hepatic de novo lipogenesis and lipid accumulation. Excessive triglyceride deposition triggers hepatocyte steatosis and lipotoxic injury, continuously activating intrahepatic inflammation and collagen deposition, gradually progressing to hepatic fibrosis, cirrhosis and even hepatocellular carcinoma, which forms the core pathological cascade driving MASH deterioration. Ervogastat selectively binds to the catalytic pocket of DGAT2 and reversibly blocks enzyme activity to directly cut off hepatic triglyceride synthesis, drastically lowering intracellular lipid levels. Phase 2 clinical imaging data confirmed that 72% subjects achieved ≥30% intrahepatic fat reduction and 61% gained over 50% lipid decline after administration, rapidly alleviating hepatic fatty infiltration. Different from single-target agents merely regulating lipid metabolism, it simultaneously suppresses hepatic pro-inflammatory cytokine release to mitigate lobular inflammatory infiltration and slow collagen proliferation. A unique merit is its capacity to counteract peripheral triglyceride elevation induced by single ACC inhibitor therapy. Combined administration targets the full hepatic lipogenesis pathway with prominent synergistic efficacy, delivering a 66% histological response rate after 48 weeks dual-target treatment, far superior to monotherapy and placebo groups.

Clinically and scientifically, Ervogastat covers two core application directions. First, it acts as a standard tool compound for fundamental MASH/NASH research, establishing steatotic cell and animal models to dissect regulatory mechanisms of DGAT2 pathway in hepatic lipid metabolism, inflammation and fibrosis, supporting high-throughput compound screening, target validation and combined regimen exploration. Second, it supports innovative oral formulation development for tablet prescription research, targeting treatment pipelines for patients with moderate F2-F3 hepatic fibrosis. It achieves systemic oral absorption with preferential inhibitory activity on hepatic lipogenesis, bringing better administration adherence than liver-localized injectable candidates. Applicable crowds include obese individuals, type 2 diabetics complicated with fatty liver and metabolic syndrome patients with liver injury, making up for the clinical shortage of radical specific medicines for fatty liver disease.

Regarding industrial production and market value, Ervogastat adopts mature patented total synthetic routes with refined purification technology to stably remove structurally related impurities, enabling controllable mass customization costs and bulk supply ranging from milligram to kilogram scale, matching full demands of lab-scale pharmacology, pilot formulation and preclinical animal efficacy studies. It demonstrates favorable overall administration tolerance without severe liver or kidney toxicity under routine doses, only occasional mild gastrointestinal adverse reactions, presenting a wide therapeutic safety window. With the global surging prevalence of obesity and diabetes leading to rapidly expanding MASH patient population, R&D enthusiasm for anti-fatty liver novel drugs keeps rising alongside growing demand for DGAT2 target raw materials. Possessing first-in-class target novelty, solid clinical data and differentiated combination therapeutic value, Ervogastat maintains irreplaceable long-term market competitiveness in liver disease pharmacological research, innovative and generic drug development and export API supply, promising stable and broad long-term development prospects across the global pharmaceutical industry.