title: 2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.
abstract: 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.
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: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Jaimie K
authors.initials: JK
authors.lastname: Rueter
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: Tanya
authors.initials: T
authors.lastname: Joswig
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
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: 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: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Zhihong
authors.initials: Z
authors.lastname: O'Brien
authors.forename: Robert
authors.initials: R
authors.lastname: Petroski
authors.forename: John
authors.initials: J
authors.lastname: Saunders
mesh_terms: 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
chemical_list: D000081:Acetamides; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D051638:Ether-A-Go-Go Potassium Channels; D011743:Pyrimidines