title: Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.
abstract: Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic β-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Elowe
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, 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 07033, USA.
authors.forename: George H
authors.initials: GH
authors.lastname: Addona
authors.affiliation: Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, 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 07033, 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 07033, USA.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery; 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; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D011725:Pyridines; D005941:Glucokinase
keywords: Diabetes; Glucokinase; Glucokinase activator (GKA); Glucose homeostasis; Glucose metabolism; Hepatoselective; Hepatospecific; Hexokinase IV; Liver preferring; Pyridine-2-carboxamide; Type II Diabetes Mellitus