G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
Computational studies of a chiral lithium amide (lithium (2-methoxy-(R)-1-phenylethyl)((S)-1-phenylethyl)amide, 3) using the solid-state structure as a reference geometry showed that there were only
small differences between the X-ray and ab initio and PM3 calculated structures. Furthermore, we have shown
that reference distances from either X-ray or ab initio/PM3 can be used for the calculation of Li−H distances
using Li−H NOE data. The calculations of Li−H distances using HOESY buildup rates showed that the
solution structure of 3·THF is similar to the structure obtained in the gas phase (calculated) and in the solid
phase (X-ray). Small variations of ±0.2 Å were observed between X-ray/ab initio and NOE data for distances
less than 4 Å.
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