1. 4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors
- Author
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Steven W. Muchmore, Elizabeth A. Kowaluk, Kennan C. Marsh, Steve McGaraughty, Haixia Yu, Arthur Gomtsyan, Andrew O. Stewart, Shripad S. Bhagwat, Michael F. Jarvis, Karen M. Alexander, Kathy L. Kohlhaas, Clarissa L. Jakob, Chih-Hung Lee, Robin R. Frey, Mark A. Matulenko, Ernest S. Paight, Joseph P. Mikusa, Meiqun Jiang, and Stanley Didomenico
- Subjects
Protein Conformation ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine kinase ,Crystallography, X-Ray ,Biochemistry ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Binding site ,Adenosine Kinase ,Molecular Biology ,Binding Sites ,biology ,Chemistry ,Aryl ,Organic Chemistry ,Active site ,Ligand (biochemistry) ,Adenosine ,Rats ,Pyrimidines ,biology.protein ,Molecular Medicine ,Nucleoside ,Protein Binding ,medicine.drug - 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.
- Published
- 2007