Discovery and optimization of imidazoline derivatives, a potent, orally active neuropeptide Y Y5 receptor antagonist

MEDI 46

Makoto Ando, Nagaaki Sato, Shiho Ishikawa, Makoto Jitsuoka, Keita Nagai, Tsuyoshi Nagase, Hirobumi Takahashi, Aya Sakuraba, Hiroyasu Tsuge, Mioko Hirayama, Junko Ito, Hisashi Iwaasa, Hiroko Matsushita, Akira Gomori, Satoshi Mashiko, Akane Ishihara, Naoko Fujino, Sachiko Tanaka, Tomoyuki Ohe, Kiyoshi Tadano, Takahiro Fukuroda, Yasuyuki Ishii, Akio Kanatani, and Takehiro Fukami. Tsukuba Research Institute, Banyu Pharmaceutical CO., LTD, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
Neuropeptide Y is a 36-amino acid peptide with centrally mediated potent orexigenic effects. Five types of NPY receptors (Y1, Y2, Y4, Y5 and y6) have been characterized, and pharmacological data suggest that the NPY Y5 receptor (Y5R), located primarily in the hypothalamus, is involved in feeding regulation. Screening of our chemical collection against the human Y5R resulted in the identification of 2,4,4-triaryl imidazoline with an IC50 value of 60 nM at the Y5. Optimization of the triarylimidazoline lead led to potent derivative 1 that is orally active in rodents. However, intravenous administration of 1 showed a significant QT prolongation in anesthetized dogs. The QT issue was overcome by further modification of 2-substituents, and clinical candidate 2 was identified. The enantioselective synthesis, SAR and in vivo data of the imidazoline derivatives will be presented.

 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007