2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents.
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.
Slee
Deborah H
DH
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. dslee@neurocrine.com
Chen
Yongsheng
Y
Zhang
Xiaohu
X
Moorjani
Manisha
M
Lanier
Marion C
MC
Lin
Emily
E
Rueter
Jaimie K
JK
Williams
John P
JP
Lechner
Sandra M
SM
Markison
Stacy
S
Malany
Siobhan
S
Santos
Mark
M
Gross
Raymond S
RS
Jalali
Kayvon
K
Sai
Yang
Y
Zuo
Zhiyang
Z
Yang
Chun
C
Castro-Palomino
Julio C
JC
Crespo
María I
MI
Prat
Maria
M
Gual
Silvia
S
Díaz
José-Luis
JL
Saunders
John
J
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
D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines