Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile

Futatsugi, Kentaro; Huard, Kim; Kung, Daniel W.; Pettersen, John C.; Flynn, Declan; Gosset, J; Aspnes, Gary E.; Barnes, Robert J.; Cabral, Shawn; Dowling, Matthew S.; Fernando, Dilinie P.; Goosen, Theunis C.; Gorczyca, William P.; Hepworth, David; Herr, Michael; Lavergne, Sophie Y.; Li, Q.; Niosi, Mark; Orr, Suvi T. M.; Pardo, Ingrid; Perez, Sylvie; Purkal, Julie J.; Schmahai, Theodore J.; Shirai, Norimitsu; Shoieb, Ahmed; Zhou, Jun; Goodwin, Bryan

doi:10.1039/c6md00564k

Cited by 9 publications

(12 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These effects seem to be unique to inhibition of DGAT2, as ASO against DGAT1 did not lead to similar beneficial effects. Collectively these data support the notion that inhibition of DGAT2 activity could have a beneficial effect on dyslipidemia and insulin sensitivity and, similarly to the case for DGAT1, this has led to the development of several diverse small-molecule inhibitors of DGAT2 as potential therapeutics (Futatsugi et al, 2015(Futatsugi et al, , 2017Kim et al, 2013). Although the liver is one of the primary sites for DGAT2 expression, DGAT1 is also expressed in the liver and the respective roles of the enzymes with regard to hepatic TG synthesis have not been well defined, especially across different species.…”

Section: Introductionsupporting

confidence: 66%

DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates

et al. 2018

View full text Add to dashboard Cite

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters. In contrast, experiments in primary human, rhesus, and cynomolgus hepatocytes demonstrated that selective inhibition of DGAT2 has only a modest effect. Acute and chronic inhibition of DGAT2 in rhesus primates recapitulated the in vitro data yielding no significant effects on production of plasma TG or VLDL apolipoprotein B. These results call into question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia.

show abstract

Section: Introductionsupporting

confidence: 66%

DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates

et al. 2018

View full text Add to dashboard Cite

show abstract

“…During the optimization of this nitro-amide route toward 1 , another compound of interest was identified ( 2 ), along with a project need to evaluate both compounds for differentiation in efficacy and safety studies. Structurally, compound 2 differs from 1 by the presence of a methyl group in place of the cyclopropane, creating a second stereocenter in the molecule.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of one or both of these enzymes has been proposed as a treatment for metabolic disease . Several small molecule inhibitors of DGAT-2 have been disclosed recently. − This manuscript describes the synthetic route development toward scalable syntheses of the imidazopyridines PF-06424439 ( 1 ) and PF-06450561 ( 2 ) which were evaluated in efficacy and safety studies, leading to decreased cholesterol and triglyceride levels in preclinical species (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Route Selection and Optimization in the Synthesis of Two Imidazopyridine Inhibitors of DGAT-2

Bader

Herr

Aspnes

et al. 2018

Org. Process Res. Dev.

View full text Add to dashboard Cite

The scalable syntheses of two imidazopyridine inhibitors of the enzyme diacylglycerol acyltransferase 2 (DGAT-2) are described. 6-Chloro-3-nitro-2-aminopyridine was the starting material for the convergent synthesis of the central imidazopyridine ring. Differentiation in reactivity of the C2-and C3-nitrogen substituents on the pyridine ring and the development of mild cyclodehydration conditions to form the imidazole ring were critical problems that were addressed to deliver a 3-kg batch of compound 1 (PF-06424439) and a 0.1-kg batch of compound 2 (PF-06450561).

show abstract

“…16−24 However, there have been very few literature reports on DGAT2 inhibitors that display in vivo efficacy. [16][17][18]24 Herein, we describe a highly reproducible and highthroughput screening-compatible DGAT2 assay, where it was critical to inhibit endogenous acyl-CoA-hydrolyzing enzyme(s) in the membrane fraction from insect cells commonly used as a source of DGAT2. For our search for novel DGAT2 inhibitors, we carried out a high-throughput screening of the Pfizer compound library and identified a new chemical series of agents that share an imidazopyridine scaffold.…”

mentioning

confidence: 99%

“…Several DGAT2 inhibitors displaying modest in vitro potency have been reported. − However, there have been very few literature reports on DGAT2 inhibitors that display in vivo efficacy. − , …”

mentioning

confidence: 99%

Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

Pabst

Futatsugi

et al. 2018

Biochemistry

View full text Add to dashboard Cite

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triacylglycerol (TAG) synthesis. Genetic knockdown or pharmacological inhibition of DGAT2 leads to a decrease in very-low-density lipoprotein TAG secretion and hepatic lipid levels in rodents, indicating DGAT2 may represent an attractive therapeutic target for treatment of hyperlipidemia and hepatic steatosis. We have previously described potent and selective imidazopyridine DGAT2 inhibitors with high oral bioavailability. However, the detailed mechanism of DGAT2 inhibition has not been reported. Herein, we describe imidazopyridines represented by PF-06424439 (1) and 2 as long residence time inhibitors of DGAT2. We demonstrate that 1 and 2 are slowly reversible, time-dependent inhibitors, which inhibit DGAT2 in a noncompetitive mode with respect to the acyl-CoA substrate. Detailed kinetic analysis demonstrated that 1 and 2 inhibit DGAT2 in a two-step binding mechanism, in which the initial enzyme–inhibitor complex (EI) undergoes an isomerization step resulting in a much higher affinity complex (EI*) with overall apparent inhibition constants (K i*app values) of 16.7 and 16.0 nM for 1 and 2, respectively. The EI* complex dissociates with dissociation half-lives of 1.2 and 1.0 h for 1 and 2, respectively. A binding assay utilizing 125I-labeled imidazopyridine demonstrated that the level of imidazopyridine binding to DGAT2 mutant enzymes, H161A and H163A, dramatically decreased to 11–17% of that of the wild-type enzyme, indicating that these residues are critical for imidazopyridines to bind to DGAT2. Taken together, imidazopyridines may thus represent a promising lead series for the development of DGAT2 inhibitors that display an unprecedented combination of potency, selectivity, and in vivo efficacy.

show abstract

Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile

Cited by 9 publications

References 40 publications

DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates

DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates

Route Selection and Optimization in the Synthesis of Two Imidazopyridine Inhibitors of DGAT-2

Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

Contact Info

Product

Resources

About