Lexicon confirms SAR of Ph Ia IBS drug

The USA's Lexicon Pharmaceuticals has reported data describing the structure-activity relationship (SAR) of a class of internally-developed compounds that includes LX1031 and others under evaluation by the company as potential treatments for irritable bowel syndrome (IBS) and other gastrointestinal disorders. LX1031 is currently being assessed in a Phase Ib 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 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 findings were presented at the American Chemical Society National Meeting and Exposition, held in Boston, Massachusetts.

"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 Sands, chief executive of Lexicon. "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."