title: Design of adenosine kinase inhibitors from the NMR-based screening of fragments.
abstract: 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.
authors: Pharmaceutical Discovery Division and Department of Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors: P J
authors: PJ
authors: Hajduk
authors: A
authors: A
authors: Gomtsyan
authors: S
authors: S
authors: Didomenico
authors: M
authors: M
authors: Cowart
authors: E K
authors: EK
authors: Bayburt
authors: L
authors: L
authors: Solomon
authors: J
authors: J
authors: Severin
authors: R
authors: R
authors: Smith
authors: K
authors: K
authors: Walter
authors: T F
authors: TF
authors: Holzman
authors: A
authors: A
authors: Stewart
authors: S
authors: S
authors: McGaraughty
authors: M F
authors: MF
authors: Jarvis
authors: E A
authors: EA
authors: Kowaluk
authors: S W
authors: SW
authors: Fesik
mesh_terms: 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
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D008024:Ligands; D000248:Adenosine Kinase