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. Although further in depth understanding of the conversion of NXT-10796 is required for further assessment of the developability of this series of prodrugs, using NXT-10796 as a tool molecule has allowed us to confirm that tissue-specific modulation of an EP4-modulated gene signature is possible, which allows for further evaluation of this therapeutic modality in rodent models of human disease.

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

The crystal structures of tert-butyl (5-chloro-penta-2,4-diyn-1-yl)carbamate, C10H12ClNO2 (II), and tert-butyl (5-iodo-penta-2,4-diyn-1-yl)carbamate, C10H12INO2 (IV), are isomorphous to previously reported structures and accordingly their mol-ecular and supra-molecular structures are similar. In the crystals of (II) and (IV), 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-X⋯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. A Cambridge Structural Database search revealed that C≡C-X⋯O=C contacts shorter than the sum of the van der Waals radii are scarce (only one structure for the C≡C-Cl⋯O=C inter-action and 13 structures for the similar C≡C-I⋯O=C inter-action).