Submitted by Armen Hareyan on Aug 23rd, 2007
Irritable Bowel Syndrome
Lexicon Pharmaceuticals described the structure-activity relationship (SAR) of a class of internally-developed compounds that includes LX1031 and other compounds under evaluation by the company as potential treatments for irritable bowel syndrome (IBS) and other gastrointestinal disorders.
LX1031 is currently under evaluation in a Phase 1b clinical trial in healthy volunteers.
Employing high-throughput screening of its proprietary chemical libraries, x-ray crystallography and medicinal chemistry, Lexicon scientists discovered and optimized a series of orally-administered, peripherally-acting small molecule inhibitors of the key enzyme responsible for producing serotonin in the gastrointestinal tract, tryptophan hydroxylase 1 (TPH1). In preclinical studies with these molecules, including LX1031, Lexicon scientists confirmed that serotonin levels could be predictably reduced in the intestine without affecting levels of the neurotransmitter in the brain, where it mediates mood and other behaviors. The data were presented here today at the American Chemical Society National Meeting and Exposition in Boston.
"Our genetic insights and chemistry expertise enabled us to discover a class of potent molecules that can inhibit TPH activity in the gastrointestinal tract while preserving normal levels of serotonin in the brain, an accomplishment we believe represents a significant advance for the field," commented Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Lexicon Pharmaceuticals. "Given serotonin's established role as a neurotransmitter modulating gastrointestinal function, these findings have allowed us to pursue a potential new mechanism for treating conditions, such as IBS, that are not well-served by current therapies."
Using Lexicon's proprietary knock-out mouse technology, company scientists established that serotonin in the brain and neurons is synthesized by TPH2, an enzyme related to but distinct from TPH1, which is responsible for the synthesis of almost all peripheral serotonin. Knock-out studies showed that mice lacking a functional TPH1 gene exhibited normal brain levels of serotonin with no detectable levels in the periphery. Importantly, the TPH1 knockout mice were healthy and exhibited no significant adverse effects.
Top-line Phase 1 clinical results for LX1031 are expected to be presented at the American College of Gastroenterology's Annual Scientific Meeting in Philadelphia in October.
Source:
Lexicon Pharmaceuticals, Inc. 