4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.

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Matulenko MA, Paight ES, Frey RR, Gomtsyan A, DiDomenico S Jr, Jiang M, Lee CH, Stewart AO, Yu H, Kohlhaas KL, Alexander KM, McGaraughty S, Mikusa J, Marsh KC, Muchmore SW, Jakob CL, Kowaluk EA, Jarvis MF, Bhagwat SS

4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.

Bioorg Med Chem. 2007 Feb 15;15(4):1586-605. Epub 2006 Dec 20.

PubMed ID

17197188 [ View in PubMed

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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-ylamin e (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-ylam ine (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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-[4-(DIMETHYLAMINO)PHENYL]-6-[(6-MORPHOLIN-4-YLPYRIDIN-3-YL)ETHYNYL]PYRIMIDIN-4-AMINE	Adenosine kinase	IC 50 (nM)	68	N/A	N/A	Details
5-[4-(DIMETHYLAMINO)PHENYL]-6-[(6-MORPHOLIN-4-YLPYRIDIN-3-YL)ETHYNYL]PYRIMIDIN-4-AMINE	Adenosine kinase	IC 50 (nM)	2	N/A	N/A	Details