title: Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3.
abstract: Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: Huard
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Allyn T
authors.initials: AT
authors.lastname: Londregan
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Tesz
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bahnck
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Magee
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Jana
authors.initials: J
authors.lastname: Polivkova
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Coffey
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Pabst
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Gosset
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Anu
authors.initials: A
authors.lastname: Nigam
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Kou
authors.initials: K
authors.lastname: Kou
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Kyuha
authors.initials: K
authors.lastname: Lee
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Herr
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Goodwin
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Perreault
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Csilla C
authors.initials: CC
authors.lastname: Jorgensen
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: George T
authors.initials: GT
authors.lastname: Tkalcevic
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Subashi
authors.affiliation: Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors; D004285:Dogs; D006801:Humans; D054833:Isoindoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D054833:Isoindoles; C000603792:PF-06471553; D013449:Sulfonamides; D014280:Triglycerides; D000217:Acyltransferases; D051048:Diacylglycerol O-Acyltransferase; C021802:2-acylglycerol O-acyltransferase