title: N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy.
abstract: In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lechner
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Tanya
authors.initials: T
authors.lastname: Joswig
authors.forename: William
authors.initials: W
authors.lastname: Kargo
authors.forename: Jaime
authors.initials: J
authors.lastname: Piercey
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Marilyn
authors.initials: M
authors.lastname: Zhao
authors.forename: Robert
authors.initials: R
authors.lastname: Petroski
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Zhihong
authors.initials: Z
authors.lastname: O'Brien
authors.forename: Kayvon
authors.initials: K
authors.lastname: Jalali
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000627:therapeutic use*; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004357:Drug Synergism; D006220:Haloperidol; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D012399:Rotation; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D006220:Haloperidol