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.
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).
Matulenko
Mark A
MA
Neuroscience Research, Global Pharmaceutical Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mark.a.matulenko@abbott.com
Lee
Chih-Hung
CH
Jiang
Meiqun
M
Frey
Robin R
RR
Cowart
Marlon D
MD
Bayburt
Erol K
EK
Didomenico
Stanley
S
Gfesser
Gregory A
GA
Gomtsyan
Arthur
A
Zheng
Guo Zhu
GZ
McKie
Jeffery A
JA
Stewart
Andrew O
AO
Yu
Haixia
H
Kohlhaas
Kathy L
KL
Alexander
Karen M
KM
McGaraughty
Steve
S
Wismer
Carol T
CT
Mikusa
Joseph
J
Marsh
Kennan C
KC
Snyder
Ronald D
RD
Diehl
Marilyn S
MS
Kowaluk
Elizabeth A
EA
Jarvis
Michael F
MF
Bhagwat
Shripad S
SS
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
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