PF-04620110 / Pfizer - LARVOL DELTA

Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology. (PubMed, Clin Ther) - P1, P1b | "Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis."

Clinical • Journal • Review • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. (PubMed, Physiol Rep) - "Here, the effects of DGAT1 and DGAT2 inhibition, alone or in combination, on dietary TAG absorption and diarrhea in mice were investigated by using a selective DGAT1 inhibitor (PF-04620110) and DGAT2 inhibitor (PF-06424439)...DGAT1/2 inhibition-induced diarrhea may be caused by intestinal barrier dysfunction due to dysregulation of the cytotoxic FA metabolism. These findings suggest that DGAT-mediated intestinal TAG synthesis is a vital step for maintaining intestinal barrier integrity under HFD feeding."

Journal • Preclinical

Pfizer pipeline (Pfizer) - Pfizer discontinued the development of PF-04620110 since August 11, 2011

Discontinued • Breast Cancer • Oncology

Effects of PF-04620110, a novel diacylglycerol acyltransferase 1 (DGAT-1) inhibitor, in type 2 diabetes (T2DM) subjects with insufficient glycemic control on metformin (ADA 2012) - Presentation time: 6/9/2012 11:30:00 AM; P1, N=48; PK was comparable to that observed previously in HOV and total exposure was similar between QD and BID; PF04620110 provided minimally additional pharmacodynamic benefit over a robust placebo effect in T2DM subjects

P1 data • Diabetes • Obesity

Development and validation of a simple and sensitive high resolution LC/MS method for determination of PF-04620110 in dog plasma: application to the pharmacokinetic study. (PubMed, Biomed Chromatogr) - "The validated method was successfully applied to the pharmacokinetic study of PF-04620110 in dogs and the results revealed that PF-04620110 was slowly eliminated from plasma with clearance of 60.81 ± 7.11 mL/h/kg for intravenous administration and 81.44 ± 25.79 mL/h/kg for oral administration. The oral bioavailability was determined to be 77.89% in dogs."

Journal • PK/PD data

PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages. (PubMed, Diabetes Metab J) - "Our results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation."

Journal

Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse. (PubMed, Xenobiotica) - "...PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice...Moreover, the in vitro metabolic elimination kinetic parameters (k), determined using liver microsomes from TH and ICR mice were 1.24 ± 0.14 and 0.174 ± 0.116 min, respectively. Thus, we report that the differences in the acute effects of the small molecule DAGT-1 inhibitor between TH mice and ICR mice can be attributed to altered pharmacokinetics caused by an altered metabolic rate for the compound in TH mice."

Journal • PK/PD data • Preclinical