Identification and design of a novel series of MGAT2 inhibitors

Barlind, Jonas G.; Buckett, Linda K.; Crosby, Sharon G.; Davidsson, Öjvind; Emtenäs, Hans; Ertan, Anne; Jurva, Ulrik; Lemurell, Malin; Gutierrez, Pablo Morentin; Nilsson, Karolina; O’Mahony, Gavin; Petersson, Annika; Redzic, Alma; Wågberg, F.; Yuan, Zhong-Qing

doi:10.1016/j.bmcl.2013.02.084

Cited by 29 publications

(31 citation statements)

References 12 publications

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“…Indeed, recently in the medicinal chemistry fi eld many papers and patents describing a number of structurally diverse small molecules as inhibitors of MGAT2 have been published (5)(6)(7)(8) . Monoacylglycerol acyltransferase-2 (MGAT2) is a membrane-bound lipid acyltransferase that is an emerging molecular target for the treatment of obesity and type 2 diabetes ( 1 ).…”

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confidence: 99%

Cell-based assay of MGAT2-driven diacylglycerol synthesis for profiling inhibitors: use of a stable isotope-labeled substrate and high-resolution LC/MS

Onorato

Chu

et al. 2015

Journal of Lipid Research

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and monoacylglycerol are used as building blocks to resynthesize TAG through two sequential acylation steps. The fi rst acylation step is performed by MGAT, followed by diacylglycerol acyltransferase (DGAT) enzyme reactions. TAGs are then incorporated into chylomicrons and secreted into lymph to be used as an energy supply for the body ( 4 ).MGAT2 KO mice exhibit a multitude of healthy metabolic phenotypes relative to WT controls, including resistance to high-fat diet-induced obesity, improvement in insulin sensitivity, and decreased fat accumulation in liver and adipose tissue ( 1 ). Under a high-fat diet regimen for 8-9 months, WT mice became diabetic, with fasting glucose levels of approximately 220 mg/dl. In contrast, littermate MGAT2 KO mice exposed to the same high-fat diet regimen exhibited signifi cantly lower fasting glucose levels ( ‫ف‬ 120 mg/dl). In addition, mice with genetic deletion of MGAT2 appeared to absorb fat at a more distal site in the intestine than WT controls, suggesting delayed TG absorption. Further, there is evidence that glucagon-like peptide-1 is elevated in MGAT2 KO mice. The mouse genetic data therefore support the concept of using MGAT2 inhibition for the treatment of type 2 diabetes through weight loss and gut hormone regulation ( 1 ).Multiple pharmaceutical companies have initiated campaigns to identify MGAT2 inhibitors as therapeutic agents to combat obesity and type 2 diabetes. Indeed, recently in the medicinal chemistry fi eld many papers and patents describing a number of structurally diverse small molecules as inhibitors of MGAT2 have been published Monoacylglycerol acyltransferase-2 (MGAT2) is a membrane-bound lipid acyltransferase that is an emerging molecular target for the treatment of obesity and type 2 diabetes ( 1 ). MGAT2 is highly and selectively expressed in the small intestine, where it exerts an important role in the monoacylglycerol pathway of triacylglycerol (TAG) synthesis for the absorption of dietary fat ( 2, 3 ). When dietary fat is ingested, pancreatic lipase digests TAG into FFAs and monoacylglycerol, which are absorbed by intestinal epithelial enterocytes. Once inside enterocytes, FFAs

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confidence: 99%

Cell-based assay of MGAT2-driven diacylglycerol synthesis for profiling inhibitors: use of a stable isotope-labeled substrate and high-resolution LC/MS

Onorato

Chu

et al. 2015

Journal of Lipid Research

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“…5 This had resulted in improvements in permeability, as assessed in a Caco-2 assay (apical pH =6.5; basolateral pH = 7.4). 8 This was consistent with a reduction in hydrogen bond donor count, but had led to an unacceptable loss in potency for the three molecular matched pairs ( Figure 1).…”

Section: Body Textmentioning

confidence: 99%

“…Our conclusion from these data was that modulation of the 9-position offered an opportunity to increase permeability (F, OMe, aza-N) and potency (Me, OMe) with methoxy offering an opportunity to do both simultaneously. Exploration of the R9 substituent ( Table 2) was carried out contemporaneously in a 2,4-fluoro aniline series which had been previously shown 5 to be considerably more potent and less lipophilic than the 4-trifluoromethyl aniline (contrast matched pair 1 and 13). Methyl substitution resulted in an increase in potency although this was less dramatic than seen previously (LLE for 10 and 1 = +1.3; LLE for 14 and 13 = +0.5).…”

Section: Body Textmentioning

confidence: 99%

“…In the 9-chloro analogue (23), similar amide interactions between the cores are retained, however, it is noteworthy that the sulphonamide H-bonding motifs are completely absent in this structure (Figure 4). Compounds were synthesized using a modified version of the previously described route 5 whereby cyclisations were carried out on the amino ester intermediates of type 29 (Scheme 1). This circumvented difficulties associated with isolation of the previously employed amino acids.…”

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confidence: 99%

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Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors

et al. 2013

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“…1, AstraZeneca's compound 1 reported in the literature showed potent MGAT2 inhibitory activity and a significant reduction of plasma TG concentration after an oral administration at a dose of 150 mg/kg in mice oral lipid tolerance test. [16][17][18] We have also reported an orally available MGAT2 inhibitor, 19) 2-[2-(4-tert-butylphenyl)-ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2, which demonstrated the significant suppression of fat absorption in mice oral lipid tolerance test at an oral dose of 100 mg/kg.The identification of compound 2 promoted us to explore a more potent and orally available MGAT2 inhibitor, and our efforts have been focused on optimization of compound 2. As…”

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Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

Busujima

Tanaka

Iwakiri

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC 50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.Key words monoacylglycerol acyltransferase 2; fat absorption; oral lipid tolerance test; tetrahydroisoquinoline A rapid increases of obesity, type 2 diabetes and cardiovascular disease have become a huge issue in the world's industrialized countries. The unmet medical need for the treatment of these diseases has promoted the identification of many new targets, one of which is the inhibition of triacylglycerol synthesis.Dietary-derived fats are degraded in the gastrointestinal tract and then taken up by small-intestinal epithelial cells. Acyl CoA : monoacylglycerol acyltransferase (MGAT), which catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA, plays a crucial role in triglyceride (TG) re-synthesis in the small intestine. 1) After re-synthesis into neutral fats in the cells, 2) the neutral fats are packaged into chylomicrons, secreted into the lymphatics, and taken up into body. Therefore, the inhibition of activity of this enzyme is expected to suppress re-synthesis of TG and lead to reduce fat absorption.Three isoforms of MGAT enzyme have been identified, [3][4][5] and MGAT2 is highly expressed in small intestine in both humans and mice.1) The phenotype of MGAT2 deficient mice has been already reported.6) These mice were viable and fertile without apparent abnormalities. After these mice were orally given dietary oil (oral lipid tolerance test), plasma TG levels of these mice were significantly lower than those of the wild type. In addition, MGAT2 knock-out mice showed resistance to obesity, glucose intolerance, and hypercholesterolemia induced by a high fat diet. Furthermore, these mice demonstrated increased oxygen consumption without high-fat feeding, and MGAT2 was expected to modulate energy expenditure. 7,8) These results implied that inhibition of MGAT2 could be an attractive mechanism for reduction of fat absorption and treatment of obesity and associated metabolic disorders.Some small molecule MGAT2 inhibitors have been disclosed. [9][10][11][12][13][14][15] As shown in Fig. 1, AstraZeneca's compound 1 reported in the literature showed potent MGAT2 inhibitory activity and a significant reduction of plasma TG concentration after an oral administration at a dose of 150 mg/kg in mice oral lipid tolerance test. [16][17][18] We have also reported an orally available MGAT2 inhibitor, 19) 2-[2-(4-tert-butylphenyl)-ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydrois...

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Identification and design of a novel series of MGAT2 inhibitors

Cited by 29 publications

References 12 publications

Cell-based assay of MGAT2-driven diacylglycerol synthesis for profiling inhibitors: use of a stable isotope-labeled substrate and high-resolution LC/MS

Cell-based assay of MGAT2-driven diacylglycerol synthesis for profiling inhibitors: use of a stable isotope-labeled substrate and high-resolution LC/MS

Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors

Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

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