title: 4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.
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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mark.a.matulenko@abbott.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Paight
authors.forename: Robin R
authors.initials: RR
authors.lastname: Frey
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Stanley
authors.initials: S
authors.lastname: DiDomenico
authors.forename: Meiqun
authors.initials: M
authors.lastname: Jiang
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Haixia
authors.initials: H
authors.lastname: Yu
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: Karen M
authors.initials: KM
authors.lastname: Alexander
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Joseph
authors.initials: J
authors.lastname: Mikusa
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Steven W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: Clarissa L
authors.initials: CL
authors.lastname: Jakob
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kowaluk
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Shripad S
authors.initials: SS
authors.lastname: Bhagwat
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D051379:Mice; D009025:Morpholines; D011485:Protein Binding; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D009025:Morpholines; D011743:Pyrimidines; C416933:ABT 702; D000248:Adenosine Kinase