title: 2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents.
abstract: Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. dslee@neurocrine.com
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Jaimie K
authors.initials: JK
authors.lastname: Rueter
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lechner
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Kayvon
authors.initials: K
authors.lastname: Jalali
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Zuo
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Julio C
authors.initials: JC
authors.lastname: Castro-Palomino
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: Maria
authors.initials: M
authors.lastname: Prat
authors.forename: Silvia
authors.initials: S
authors.lastname: Gual
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: John
authors.initials: J
authors.lastname: Saunders
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines