Design of adenosine kinase inhibitors from the NMR-based screening of fragments.
A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.
Hajduk
P J
PJ
Pharmaceutical Discovery Division and Department of Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Gomtsyan
A
A
Didomenico
S
S
Cowart
M
M
Bayburt
E K
EK
Solomon
L
L
Severin
J
J
Smith
R
R
Walter
K
K
Holzman
T F
TF
Stewart
A
A
McGaraughty
S
S
Jarvis
M F
MF
Kowaluk
E A
EA
Fesik
S W
SW
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D004791:Enzyme Inhibitors; D008024:Ligands; D000248:Adenosine Kinase