Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT(4) receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation.

Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.

Conformational Analysis of 2-Substituted Alkylphosphoryl Compounds. 4. Substituent Effect on the Nature of the Hydrogen Bonding in (2-Hydroxyalkyl)phosphoryl Systems.

The extent to which solid state conformational and hydrogen bonding preferences of five (2-hydroxyalkyl)phosphoryl compounds 2a-e [R(1)(2)P(O)CH(2)CH(OH)R(2); 2a, R(1) = MeO, R(2) = Ph; 2b, R(1) = R(2) = Ph; 2c, R(1) = Ph, R(2) = Bu(t); 2d, R(1) = Me, R(2) = Ph; 2e, R(1) = Me, R(2) = Bu(t)] change upon dissolution has been investigated using X-ray crystallography, IR, and NMR spectroscopy. Intermolecular hydrogen bonding involving inversion-center-related cyclic dimers is shown to be a common solid state arrangement, with relatively small structural changes producing infinite chains. Intramolecular hydrogen bonded monomers are uncommon.