Modulation of peripheral serotonin levels by enzyme inhibitors for the potential treatment of irritable bowel syndrome (IBS)

MEDI 235

Zhi-Cai Shi, zshi@lexpharma.com1, Raj Devasagayaraj1, Kunjian Gu1, Haihong Jin1, S David Kimball1, Brett Marinelli1, Lakshman Samala1, Sheldon Scott1, Ashok Tunoori1, Ying Wang1, Yi Zang1, Chengmin Zhang1, Terry Stouch1, Jim Liu2, Dave Powell3, Weimei Sun2, Melissa Yang3, Amr Nouraldeen4, Alan Wilson4, and Xiang-Qing Yu4. (1) Department of Medicinal Chemistry, Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, (2) Department of Pharmaceutical Discovery, Lexicon Genetics, 4000 Research Forest Drive, The Woodlands, TX 77381, (3) Department of Pharmaceutical Biology, Lexicon Genetics, 4000 Research Forest Drive, The Woodlands, 77381, (4) Department of Drug Metabolism and Pharmacokinetics, Lexicon Genetics
Using mouse knockout technology, Lexicon has identified an enzyme found predominantly in the gastrointestinal (GI) tract that regulates peripheral serotonin levels. Inhibitors of this enzyme dose-dependently reduce the concentration of serotonin in the GI tract in multiple species, without affecting serotonin levels in the brain. By lowering serotonin concentrations and reducing activation of serotonergic receptors in peripheral tissues, these inhibitors should be useful in the treatment of irritable bowel syndrome (IBS). IBS is a common gastrointestinal disorder characterized by pain, discomfort and motility problems that affects between 10-20% of adults in the United States. The discovery and SAR of a series of compounds that inhibit this target will be discussed.
 

General Oral Session
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

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