title: 2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists.
abstract: The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. BShirema@prdus.jnj.com <BShirema@prdus.jnj.com>
authors.forename: Brock T
authors.initials: BT
authors.lastname: Shireman
authors.forename: Curt A
authors.initials: CA
authors.lastname: Dvorak
authors.forename: Dale A
authors.initials: DA
authors.lastname: Rudolph
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.forename: Lisa
authors.initials: L
authors.lastname: Dvorak
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Miller
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists