Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4325-9. doi: 10.1016/j.bmcl.2009.05.069.
Minoru Kameda  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
PMID: 19487123 DOI: 10.1016/j.bmcl.2009.05.069
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.