2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Slee
Deborah H
DH
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. dslee@neurocrine.com
Moorjani
Manisha
M
Zhang
Xiaohu
X
Lin
Emily
E
Lanier
Marion C
MC
Chen
Yongsheng
Y
Rueter
Jaimie K
JK
Lechner
Sandra M
SM
Markison
Stacy
S
Malany
Siobhan
S
Joswig
Tanya
T
Santos
Mark
M
Gross
Raymond S
RS
Williams
John P
JP
Castro-Palomino
Julio C
JC
Crespo
María I
MI
Prat
Maria
M
Gual
Silvia
S
Díaz
José-Luis
JL
Jalali
Kayvon
K
Sai
Yang
Y
Zuo
Zhiyang
Z
Yang
Chun
C
Wen
Jenny
J
O'Brien
Zhihong
Z
Petroski
Robert
R
Saunders
John
J
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D051638:Ether-A-Go-Go Potassium Channels; D011743:Pyrimidines