Title of article :
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 Original Research Article
Author/Authors :
Mark A. Matulenko، نويسنده , , Chih-Hung Lee، نويسنده , , Meiqun Jiang، نويسنده , , Robin R. Frey، نويسنده , , Marlon D. Cowart، نويسنده , , Erol K. Bayburt، نويسنده , , Stanley DiDomenico، نويسنده , , Gregory A. Gfesser، نويسنده , , Arthur Gomtsyan، نويسنده , , Guo Zhu Zheng، نويسنده , , Jeffery A. McKie، نويسنده , , Andrew O. Stewart، نويسنده , , Haixia Yu، نويسنده , , Kathy L. Kohlhaas، نويسنده , , Karen M. Alexander، نويسنده , , Steve McGaraughty، نويسنده , , Carol T. Wismer، نويسنده , , Joseph Mikusa، نويسنده , , Kennan C. Marsh، نويسنده , , Ronald D. Snyder، نويسنده , , et al.، نويسنده ,
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).
