title: 5-(3-Bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine: structure-activity relationships of 7-substituted heteroaryl analogs as non-nucleoside adenosine kinase inhibitors.
abstract: 4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mark.a.matulenko@abbott.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Meiqun
authors.initials: M
authors.lastname: Jiang
authors.forename: Robin R
authors.initials: RR
authors.lastname: Frey
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Stanley
authors.initials: S
authors.lastname: Didomenico
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gfesser
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Guo Zhu
authors.initials: GZ
authors.lastname: Zheng
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: McKie
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Haixia
authors.initials: H
authors.lastname: Yu
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: Karen M
authors.initials: KM
authors.lastname: Alexander
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Carol T
authors.initials: CT
authors.lastname: Wismer
authors.forename: Joseph
authors.initials: J
authors.lastname: Mikusa
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Snyder
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Diehl
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kowaluk
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Shripad S
authors.initials: SS
authors.lastname: Bhagwat
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C505383:5-(3-Bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido(2,3-d)pyrimidin-4-ylamine; D004791:Enzyme Inhibitors; D009025:Morpholines; D011743:Pyrimidines; D000248:Adenosine Kinase