Discovery of Tetralones As Potent and Selective Inhibitors of Acyl-CoA:Diacylglycerol Acyltransferase 1

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Feb 20

PMID 29456796

Citations 2

Authors

Mui Cheung

Raghuram S Tangirala

Sridhar R Bethi

Hemant V Joshi

Jennifer L Ariazi

Vijaya G Tirunagaru

Sanjay Kumar

Affiliations

Soon will be listed here.

Abstract

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays an important role in triglyceride synthesis and is a target of interest for the treatment of metabolic disorders. Herein we describe the structure-activity relationship of a novel tetralone series of DGAT1 inhibitors and our strategies for overcoming genotoxic liability of the anilines embedded in the chemical structures, leading to the discovery of a candidate compound, ()-2-(6-(5-(3-(3,4-difluorophenyl)ureido)pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid (GSK2973980A, ). Compound is a potent and selective DGAT1 inhibitor with excellent DMPK profiles and efficacy in a postprandial lipid excursion model in mice. Based on the overall biological and developability profiles and acceptable safety profiles in the 7-day toxicity studies in rats and dogs, compound was selected as a candidate compound for further development in the treatment of metabolic disorders.

Citing Articles

Efficient access to aliphatic esters by photocatalyzed alkoxycarbonylation of alkenes with alkyloxalyl chlorides.

Chen J, Tu X, Tang Q, Li K, Xu L, Wang S Nat Commun. 2021; 12(1):5328.

PMID: 34493725 PMC: 8423752. DOI: 10.1038/s41467-021-25628-x.

A novel role for DGATs in cancer.

Hernandez-Corbacho M, Obeid L Adv Biol Regul. 2018; 72:89-101.

PMID: 30579761 PMC: 6488436. DOI: 10.1016/j.jbior.2018.12.001.

References

Fioravanzo E, Bassan A, Pavan M, Mostrag-Szlichtyng A, Worth A . Role of in silico genotoxicity tools in the regulatory assessment of pharmaceutical impurities. SAR QSAR Environ Res. 2012; 23(3-4):257-77. DOI: 10.1080/1062936X.2012.657236. View

Smith S, Cases S, JENSEN D, Chen H, Sande E, Tow B . Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet. 2000; 25(1):87-90. DOI: 10.1038/75651. View

Zhang X, Yan J, Yan G, Sun X, Ji J, Li Y . Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight gain, hyperlipidemia, and hepatic steatosis in db/db mice. Acta Pharmacol Sin. 2010; 31(11):1470-7. PMC: 4003326. DOI: 10.1038/aps.2010.104. View

Denison H, Nilsson C, Lofgren L, Himmelmann A, Martensson G, Knutsson M . Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obes Metab. 2013; 16(4):334-43. DOI: 10.1111/dom.12221. View

Denison H, Nilsson C, Kujacic M, Lofgren L, Karlsson C, Knutsson M . Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study. Diabetes Obes Metab. 2012; 15(2):136-43. DOI: 10.1111/dom.12002. View

Chen H, Farese Jr R . Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 25(3):482-6. DOI: 10.1161/01.ATV.0000151874.81059.ad. View

Naik R, Obiang-Obounou B, Kim M, Choi Y, Lee H, Lee K . Therapeutic strategies for metabolic diseases: Small-molecule diacylglycerol acyltransferase (DGAT) inhibitors. ChemMedChem. 2014; 9(11):2410-24. DOI: 10.1002/cmdc.201402069. View

Chen H, Farese Jr R . Fatty acids, triglycerides, and glucose metabolism: recent insights from knockout mice. Curr Opin Clin Nutr Metab Care. 2002; 5(4):359-63. DOI: 10.1097/00075197-200207000-00002. View

MARON D, Ames B . Revised methods for the Salmonella mutagenicity test. Mutat Res. 1983; 113(3-4):173-215. DOI: 10.1016/0165-1161(83)90010-9. View

10.

Ohshiro T, Tomoda H . Acyltransferase inhibitors: a patent review (2010-present). Expert Opin Ther Pat. 2014; 25(2):145-58. DOI: 10.1517/13543776.2014.989833. View

11.

Dow R, Li J, Pence M, Gibbs E, LaPerle J, Litchfield J . Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med Chem Lett. 2014; 2(5):407-12. PMC: 4018057. DOI: 10.1021/ml200051p. View

12.

Birch A, Groombridge S, Law R, Leach A, Mee C, Schramm C . Rationally designing safer anilines: the challenging case of 4-aminobiphenyls. J Med Chem. 2012; 55(8):3923-33. DOI: 10.1021/jm3001295. View

13.

Villanueva C, Monetti M, Shih M, Zhou P, Watkins S, Bhanot S . Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology. 2009; 50(2):434-42. PMC: 3097135. DOI: 10.1002/hep.22980. View

14.

DeVita R, Pinto S . Current status of the research and development of diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors. J Med Chem. 2013; 56(24):9820-5. DOI: 10.1021/jm4007033. View