title: Structure-based design of inhibitors of purine nucleoside phosphorylase. 3. 9-Arylmethyl derivatives of 9-deazaguanine substituted on the methylene group.
abstract: X-ray crystallography and computer-assisted molecular modeling (CAMM) studies aided in the design of a potent series of mammalian purine nucleoside phosphorylase (PNP) inhibitors. Enhanced potency was achieved by designing substituted 9-(arylmethyl)-9-deazaguanine analogs that interact favorably with all three of the binding subsites of the PNP active site, namely the purine binding site, the hydrophobic pocket, and the phosphate binding site. The most potent PNP inhibitor prepared during our investigation, (S)-9-[1-(3-chlorophenyl)-2-carboxyethyl]-9-deazaguanine (18b), was shown to have an IC50 of 6 nM, whereas the corresponding (R)-isomer was 30-fold less potent.
authors.affiliation: BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 35244.
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
authors.forename: S
authors.initials: S
authors.lastname: Niwas
authors.forename: J D
authors.initials: JD
authors.lastname: Rose
authors.forename: S
authors.initials: S
authors.lastname: Ananthan
authors.forename: M
authors.initials: M
authors.lastname: Allen
authors.forename: J A
authors.initials: JA
authors.lastname: Secrist
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.forename: C E
authors.initials: CE
authors.lastname: Bugg
authors.forename: W C
authors.initials: WC
authors.lastname: Guida
authors.forename: S E
authors.initials: SE
authors.lastname: Ealick
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010710:Phosphates / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010710:Phosphates; D011687:Purines; D011743:Pyrimidines; D011758:Pyrroles; C084665:3-(2-amino-4-oxo-3H,5H-pyrrolo(3,2-d)pyrimidin-7-yl)-3-(3-chlorophenyl)propanoic acid; D006147:Guanine; C076777:9-deazaguanine; D011683:Purine-Nucleoside Phosphorylase