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Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity |
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| Authors: | Minoru Kameda Kensuke Kobayashi Hirokatsu Ito Hiroshi Miyazoe Toshiaki Tsujino Chisato Nakama Hiroshi Kawamoto Makoto Ando Sayaka Ito Tomoki Suzuki Tetsuya Kanno Takeshi Tanaka Yoshio Tahara Takeshi Tani Sachiko Tanaka Shigeru Tokita Nagaaki Sato |
| Institution: | 1. Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan;2. Department of Metabolic Disorder, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan;3. Department of Pharmacology, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan;4. Department of Drug Metabolism, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan |
| Abstract: | The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure–activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability. |
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