4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors
| Autor: | 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, Stanley Didomenico |
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| Rok vydání: | 2007 |
| Předmět: |
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 |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:1586-1605 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2006.12.029 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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