Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: Variations on the 1H-pyrimidin-2-one theme

In our efforts to further pursue one of the most selective dopamine D3-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D3 antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited Ki values toward the D3 receptor in the nano- to subnanomolar range and high selectivity versus the related D2 dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F = 37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D3 versus D2 selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F < 10%). These data significantly enhance our understanding of the D3 pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.

Graphical abstractSynthesis and SAR of highly potent and selective D3 antagonists based on a 1H-pyridin-2-one or on a urea scaffold are described. Thus, 7b displays oral bioavailability as well as brain penetration in rat. These data significantly enhance our understanding of the D3 pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.Figure optionsDownload full-size imageDownload as PowerPoint slide