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Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core |
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| Authors: | Shen Dong-Ming Brady Edward J Candelore Mari R Dallas-Yang Qing Ding Victor D-H Feeney William P Jiang Guoquiang McCann Margaret E Mock Steve Qureshi Sajjad A Saperstein Richard Shen Xiaolan Tong Xinchun Tota Laurie M Wright Michael J Yang Xiaodong Zheng Song Chapman Kevin T Zhang Bei B Tata James R Parmee Emma R |
| Institution: | a Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, RY50G-346, Rahway, NJ 07065, USA b Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA c Department of Metabolic Disorders and Molecular Endocrinology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA d Laboratory Animal Resourcesd, Merck Research Laboratories, PO Box 2000, RY50G-346 Rahway, NJ 07065, USA |
| Abstract: | A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively. |
| Keywords: | Glucagon receptor antagonists Pyrazole Diabetes |
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