4-[2-Amino-6-[(1R)-2,2,2-trifluoro-1-(3'-methoxy[1,1'-biphenyl]-4-yl)ethoxy]-4-pyrimidinyl]-L-phenylalanine

Biological Activity

tryptophan hydroxylase (tph) is a key enzyme in the synthesis of serotonin. serotonin plays important physiological roles both peripherally and centrally. lx-1031 is a heterocyclic substituted phenylalanine analog, an oral small molecule tryptophan hydroxylase (tph) inhibitor that reduces synthesis of serotonin (5-ht) peripherally and is being developed for conditions characterized by excess 5-ht expression such as diarrhea-predominant irritable bowel syndrome (ibs-d) and, possibly, carcinoid diarrhea.

in vitro

lx-1031 inhibits tph1 at its concentration of 10-8–10-7 mol l-1 range [1].

in vivo

with oral administration of lx-1031 in mice, the 5-ht reductions in the jejunum relative to control were ~33%, 51%, and 66% with the 15, 45 and 135 mg/kg/day doses, respectively; the effect of 5 mg/kg/day on gi 5-ht content was not significantly different from control [2].

target

TPH

References

[1] camilleri m. lx-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin. neurogastroenterol motil. 2011;23(3):193-200.
[2] brown pm, jackson ji, frazier ks, turner ca, shi zc, liu q. from mouse knockout to investigational drug: lx1031, a novel potential treatment for irritable bowel syndrome. am j gastroenterol 2007; 102: s961 (abstract).
[3] freiman j, jackson j, frazier ks, yang qm, liu q, brown p. lx1031: inhibition of 5-ht synthesis as a new target in the management of irritable bowel syndrome (ibs). neurogastroenterol motil 2009; 21: 250.