PF-04620110 is an orally bioavailable inhibitor of acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) reported by Pfizer. DGAT1 catalyzes the final committed step in triglyceride synthesis. The compound has the formula C21H24N4O4 and a molecular weight of 396.44 g/mol.
The PF-04620110 molecular structure contains a 4-aminopyrimidooxazepinone core and a cyclohexylacetic acid side chain. Its seven-membered oxazepinone replaced the fused oxazine ring of an earlier lead while retaining the pharmacophore arrangement.
Application of PF-04620110
Pfizer PF-04620110 is used to examine how DGAT1 inhibition affects triglyceride synthesis, intestinal lipid handling, postprandial lipids, and gut hormone release. It complements knockout models by permitting acute, dose-dependent intervention. It has also been used to study links between DGAT1-dependent lipid metabolism and NLRP3 signaling in macrophages.
In Vitro
For molar solution preparation, the PF-04620110 molecular weight is 396.44 g/mol. The compound inhibited human DGAT1 with an IC50 of 19 nM and DGAT1-mediated triglyceride synthesis in HT-29 cells with an IC50 of 8 nM. It showed more than 100-fold selectivity over DGAT2, ACAT1, ACAT2, and MGAT2.
In lipopolysaccharide-primed mouse bone-marrow-derived macrophages, it reduced IL-1β and IL-18 release in response to palmitate and other NLRP3 stimuli but did not suppress AIM2- or NLRC4-dependent activation. These findings are specific to the tested cell model and conditions.
In Vivo
In rodent lipid-challenge studies, oral PF-04620110 reduced the postprandial rise in plasma triglycerides. In mice given corn oil, PF-04620110 increased GLP-1 and PYY exposure and attenuated GIP. Orlistat blunted these responses, indicating a requirement for luminal triglyceride hydrolysis. Co-administration with sitagliptin produced a larger increase in active GLP-1 than either inhibitor alone.
Phase I studies evaluated PF-04620110 in healthy and overweight volunteers and in participants with obesity or type 2 diabetes. They documented human exposure but did not establish therapeutic efficacy.
Biochemical and Physiological Actions
DGAT1 transfers a fatty acyl group from acyl-CoA to diacylglycerol. The PF-04620110 chemical structure was optimized to inhibit this reaction selectively. In intestinal enterocytes, DGAT1 inhibition reduces triglyceride resynthesis and alters intestinal lipid processing and downstream gut-hormone signaling. The resulting signals are associated with increased GLP-1 and PYY secretion and a lower postprandial GIP response in mice.
GPR119-deficient mice showed a diminished, but not eliminated, hormone response to PF-04620110. The evidence therefore supports partial involvement of GPR119, not a direct or exclusive mechanism. Other metabolic and inflammatory findings should also be interpreted within the models and dosing regimens used.
Features and Benefits of PF-04620110
Nanomolar potency, selectivity over related acyltransferases, oral activity, and data from biochemical, cellular, animal, and Phase I studies make the compound a useful benchmark inhibitor. It can link DGAT1 inhibition to lipid, gut-hormone, and inflammasome readouts. The defined PF-04620110 structure and CAS 1109276-89-2 support literature matching, while batch-specific identity and quality should be checked in the relevant CoA and product documentation.
Powered by Bioz