Title of article :
4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors Original Research Article
Author/Authors :
Mark A. Matulenko، نويسنده , , Ernest S. Paight، نويسنده , , Robin R. Frey، نويسنده , , Arthur Gomtsyan، نويسنده , , Stanley DiDomenico Jr.، نويسنده , , Meiqun Jiang، نويسنده , , Chih-Hung Lee، نويسنده , , Andrew O. Stewart، نويسنده , , Haixia Yu، نويسنده , , Kathy L. Kohlhaas، نويسنده , , Karen M. Alexander، نويسنده , , Steve McGaraughty، نويسنده , , Joseph Mikusa، نويسنده , , Kennan C. Marsh، نويسنده , , Steven W. Muchmore، نويسنده , , Clarissa L. Jakob، نويسنده , , Elizabeth A. Kowaluk، نويسنده , , Michael F. Jarvis، نويسنده , , Shripad S. Bhagwat، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2007
Pages :
20
From page :
1586
To page :
1605
Abstract :
A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure–activity relationships and unique ligand orientation and protein conformation are discussed.
Keywords :
Glycocluster , Carbosilane dendrimer , Lactotriaose , WGA
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2007
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1305367
Link To Document :
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