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Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.
Xu, Jiayi; Lin, Songnian; Myers, Robert W; Trujillo, Maria E; Pachanski, Michele J; Malkani, Sunita; Chen, Hsuan-Shen; Chen, Zhesheng; Campbell, Brian; Eiermann, George J; Elowe, Nadine; Farrer, Brian T; Feng, Wen; Fu, Qinghong; Kats-Kagan, Roman; Kavana, Michael; McMasters, Daniel R; Mitra, Kaushik; Tong, Xinchun; Xu, Libo; Zhang, Fengqi; Zhang, Rui; Addona, George H; Berger, Joel P; Zhang, Bei; Parmee, Emma R.
Afiliación
  • Xu J; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: Jiayi_xu@merck.com.
  • Lin S; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: songnian_lin@merck.com.
  • Myers RW; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Trujillo ME; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Pachanski MJ; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Malkani S; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Chen HS; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Chen Z; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Campbell B; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Eiermann GJ; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Elowe N; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Farrer BT; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Feng W; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Fu Q; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Kats-Kagan R; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Kavana M; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • McMasters DR; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Mitra K; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Tong X; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Xu L; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Zhang F; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Zhang R; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Addona GH; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Berger JP; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Zhang B; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • Parmee ER; Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett ; 27(9): 2063-2068, 2017 05 01.
Article en En | MEDLINE | ID: mdl-28284809
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 ß-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 liverpancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Activadores de Enzimas / Diabetes Mellitus Tipo 2 / Glucoquinasa / Hipoglucemiantes Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Activadores de Enzimas / Diabetes Mellitus Tipo 2 / Glucoquinasa / Hipoglucemiantes Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article