4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.
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.
Matulenko
Mark A
MA
Neuroscience Research, Global Pharmaceutical Research Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mark.a.matulenko@abbott.com
Paight
Ernest S
ES
Frey
Robin R
RR
Gomtsyan
Arthur
A
DiDomenico
Stanley
S
Jiang
Meiqun
M
Lee
Chih-Hung
CH
Stewart
Andrew O
AO
Yu
Haixia
H
Kohlhaas
Kathy L
KL
Alexander
Karen M
KM
McGaraughty
Steve
S
Mikusa
Joseph
J
Marsh
Kennan C
KC
Muchmore
Steven W
SW
Jakob
Clarissa L
CL
Kowaluk
Elizabeth A
EA
Jarvis
Michael F
MF
Bhagwat
Shripad S
SS
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
D009025:Morpholines; D011743:Pyrimidines; C416933:ABT 702; D000248:Adenosine Kinase