title: Design and characterization of optimized adenosine A₂A/A₁ receptor antagonists for the treatment of Parkinson's disease.
abstract: The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
authors.affiliation: Janssen Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, United States. bshook@its.jnj.com
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shook
authors.forename: Stefanie
authors.initials: S
authors.lastname: Rassnick
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Wallace
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crooke
authors.forename: Mark
authors.initials: M
authors.lastname: Ault
authors.forename: Devraj
authors.initials: D
authors.lastname: Chakravarty
authors.forename: J Kent
authors.initials: JK
authors.lastname: Barbay
authors.forename: Aihua
authors.initials: A
authors.lastname: Wang
authors.forename: Mark T
authors.initials: MT
authors.lastname: Powell
authors.forename: Kristi
authors.initials: K
authors.lastname: Leonard
authors.forename: Vernon
authors.initials: V
authors.lastname: Alford
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Karen
authors.initials: K
authors.lastname: Carroll
authors.forename: Lisa
authors.initials: L
authors.lastname: Lampron
authors.forename: Lori
authors.initials: L
authors.lastname: Westover
authors.forename: Heng-Keang
authors.initials: HK
authors.lastname: Lim
authors.forename: Ronald
authors.initials: R
authors.lastname: Russell
authors.forename: Shawn
authors.initials: S
authors.lastname: Branum
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Wells
authors.forename: Sandra
authors.initials: S
authors.lastname: Damon
authors.forename: Scott
authors.initials: S
authors.lastname: Youells
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Derek A
authors.initials: DA
authors.lastname: Beauchamp
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rhodes
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jackson
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D015195:Drug Design; D005260:Female; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C571536:2-amino-8-(2-morpholinoethoxy)-4-phenyl-5H-indeno(1,2-d)pyrimidin-5-one; C571535:2-amino-8-(4-methylpiperazine-1-carbonyl)-4-phenyl-5H-indeno(1,2-d)pyrimidin-5-one; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D007192:Indenes; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A