Discovery of nicotinamides and related derivatives as potent and selective NCX reverse mode inhibitors

MEDI 452

Akio Kakefuda, akio.kakefuda@jp.astellas.com1, Takahiro Kuramochi1, Hiroyoshi Yamada1, Ippei Sato1, Issei Tsukamoto1, Taku Taguchi2, and Shuichi Sakamoto3. (1) Drug Discovery Research, Astellas Pharma Inc, 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan, (2) QA, RA and Pharmacovigilance, Astellas Pharma Inc, 3-17-1 Hasune, Itabashi, Tokyo, 174-8612, Japan, (3) Technology, Astellas Pharma Inc, 3-17-1 Hasune, Itabashi, Tokyo, 174-8612, Japan
The Na+/Ca2+ exchanger (NCX) is one of the cation transporters and plays an important role in calcium handling in cardiomyocytes. NCX typically functions in a Ca2+ extrusion (forward) mode but can also function in a Ca2+ influx (reverse) mode. In myocardial ischemia and reperfusion, increases in [Na+]i lead to arrhythmogenic calcium overload via NCX reverse mode. Therefore, inhibition of NCX reverse mode could provide a novel therapeutic approach to the treatment of arrhythmias. In our research for novel NCX reverse mode inhibitors, we chose a known NCX inhibitor as a lead and performed conventional structural modifications on the compound resulting in the identification of potent, selective and orally active NCX reverse mode inhibitors. This presentation will describe the synthesis and pharmacological characterization of nicotinamides and related derivatives.
 

Antiarrhythmic Agents
9:00 AM-12:00 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

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