Discovery of NXT-10796, an orally active, intestinally restricted EP4 agonist prodrug for the treatment of inflammatory bowel disease.

A property-focused optimization strategy was employed to modify the carboxylic acid head group of a class of EP4 agonists in order to minimize its absorption upon oral administration. The resulting oxalic acid monohydrazide-derived carboxylate isostere demonstrated utility as a class of prodrug showing colon-targeted delivery of parent agonist 2, with minimal exposure observed in the plasma. Oral administration of NXT-10796 demonstrated tissue specific activation of the EP4 receptor through modulation of immune genes in the colon, without modulation of EP4 driven biomarkers in the plasma compartment.

Isomorphous crystal structures of chlorodi-acetyl-ene and iododi-acetyl-ene derivatives: simultaneous hydrogen and halogen bonds on carbon-yl.

The crystal structures of -butyl (5-chloro-penta-2,4-diyn-1-yl)carbamate, CHClNO (), and -butyl (5-iodo-penta-2,4-diyn-1-yl)carbamate, CHINO (), are isomorphous to previously reported structures and accordingly their mol-ecular and supra-molecular structures are similar. In the crystals of () and (), mol-ecules are linked into very similar two-dimensional wall organizations with anti-parallel carbamate groups involved in a combination of hydrogen and halogen bonds (bifurcated N-H⋯O=C and C≡C-⋯O=C inter-actions on the same carbonyl group). There is no long-range parallel stacking of diynes, so the topochemical polymerization of di-acetyl-ene is prevented.