title: Design, synthesis, and structure-activity relationships of the first highly potent, selective, and bioavailable adenosine 5'-monophosphate deaminase inhibitors.
abstract: Structure-activity studies have been performed to optimize the potency of this novel series of AMPDA inhibitors. Conformational rigidification of the N-3 sidechain resulted in substantial effect on the potency. Addition of the hydrophobic groups provided further benefit. The most potent compound identified, 4g (Ki = 3 nM), bears little structural resemblance to AMP and exhibits a remarkable improvement (10(3) and 10(5)) in binding affinity relative to the original lead and AMP, respectively. The application of prodrug strategy achieved a large improvement (benzyl ester 5d) in oral bioavailability, resulting in compounds that should be useful in evaluating the role of AMPDA in normo- and pathophysiological states.
authors.affiliation: Metabasis Therapeutics Inc., San Diego, California 92121, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Kasibhatla
authors.forename: B C
authors.initials: BC
authors.lastname: Bookser
authors.forename: J R
authors.initials: JR
authors.lastname: Appleman
authors.forename: G
authors.initials: G
authors.lastname: Probst
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.forename: J M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000659:AMP Deaminase / Q000037:antagonists & inhibitors*; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000249:Adenosine Monophosphate / Q000737:chemistry; D000284:Administration, Oral; D001682:Biological Availability; D003070:Coformycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D019277:Entropy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D003070:Coformycin; D000249:Adenosine Monophosphate; D000659:AMP Deaminase; D000225:Adenine