title: Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme.
abstract: In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) 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 D(3) versus D(2) 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 D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.
authors.affiliation: Abbott GmbH & Co. KG, Discovery Research, D-67008 Ludwigshafen, Germany. herve.geneste@abbott.com
authors.forename: Hervé
authors.initials: H
authors.lastname: Geneste
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Amberg
authors.forename: Gisela
authors.initials: G
authors.lastname: Backfisch
authors.forename: Armin
authors.initials: A
authors.lastname: Beyerbach
authors.forename: Wilfried M
authors.initials: WM
authors.lastname: Braje
authors.forename: Jürgen
authors.initials: J
authors.lastname: Delzer
authors.forename: Andreas
authors.initials: A
authors.lastname: Haupt
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Linda L
authors.initials: LL
authors.lastname: King
authors.forename: Daryl R
authors.initials: DR
authors.lastname: Sauer
authors.forename: Liliane
authors.initials: L
authors.lastname: Unger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wernet
mesh_terms: D001682:Biological Availability; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; D011744:Pyrimidinones; D050637:Receptors, Dopamine D3