title: Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus.
abstract: Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic β-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA. Electronic address: Jiayi_xu@merck.com.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Xu
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA. Electronic address: songnian_lin@merck.com.
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Myers
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: George
authors.initials: G
authors.lastname: Addona
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Hsuan-Shen
authors.initials: HS
authors.lastname: Chen
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Zhesheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Nadine H
authors.initials: NH
authors.lastname: Elowe
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Farrer
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Feng
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Kats-Kagan
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kavana
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Malkani
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Michele J
authors.initials: MJ
authors.lastname: Pachanski
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Trujillo
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Libo
authors.initials: L
authors.lastname: Xu
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Fengqi
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D005941:Glucokinase
keywords: 2,5,6-Trisubstituted indole; Allosteric activator; Antidiabetic; Diabetes; Glucokinase; Glucokinase activator (GKA); Glucose homeostasis; Glucose phosphorylation; Hexokinase IV; Type 2 Diabetes Mellitus