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A novel series of indazole-/indole-based glucagon receptor antagonists.
Lin, Songnian; Zhang, Fengqi; Jiang, Guoqiang; Qureshi, Sajjad A; Yang, Xiaodong; Chicchi, Gary G; Tota, Laurie; Bansal, Alka; Brady, Edward; Trujillo, Maria; Salituro, Gino; Miller, Corey; Tata, James R; Zhang, Bei B; Parmee, Emma R.
Afiliación
  • Lin S; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: songnian.lin@merck.com.
  • Zhang F; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Jiang G; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Qureshi SA; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Yang X; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Chicchi GG; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Tota L; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Bansal A; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Brady E; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Trujillo M; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Salituro G; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Miller C; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Tata JR; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Zhang BB; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • Parmee ER; Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
Bioorg Med Chem Lett ; 25(19): 4143-7, 2015 Oct 01.
Article en En | MEDLINE | ID: mdl-26303893
ABSTRACT
A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores de Glucagón / Indazoles / Indoles Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores de Glucagón / Indazoles / Indoles Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article