title: Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides.
abstract: Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
authors.affiliation: Department of Chemistry, Vernalis (R&D) Ltd, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Gillespie
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Bamford
authors.forename: Alex
authors.initials: A
authors.lastname: Clay
authors.forename: Suneel
authors.initials: S
authors.lastname: Gaur
authors.forename: Tim
authors.initials: T
authors.lastname: Haymes
authors.forename: Philip S
authors.initials: PS
authors.lastname: Jackson
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Burkhard
authors.initials: B
authors.lastname: Klenke
authors.forename: Stefania
authors.initials: S
authors.lastname: Leonardi
authors.forename: Jeanette
authors.initials: J
authors.lastname: Liu
authors.forename: Howard L
authors.initials: HL
authors.lastname: Mansell
authors.forename: Sean
authors.initials: S
authors.lastname: Ng
authors.forename: Mona
authors.initials: M
authors.lastname: Saadi
authors.forename: Heather
authors.initials: H
authors.lastname: Simmonite
authors.forename: Gemma C
authors.initials: GC
authors.lastname: Stratton
authors.forename: Richard S
authors.initials: RS
authors.lastname: Todd
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williamson
authors.forename: Ian A
authors.initials: IA
authors.lastname: Yule
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A