title: X-ray structures of two xanthine inhibitors bound to PEPCK and N-3 modifications of substituted 1,8-dibenzylxanthines.
abstract: The analysis of the X-ray structures of two xanthine inhibitors bound to PEPCK and a comparison to the X-ray structure of GTP bound to PEPCK are reported. The SAR at N-1, N-7 and developing SAR at C-8 are consistent with information gained from the X-ray structures of compounds 1 and 2 bound to PEPCK. Representative N-3 modifications of compound 2 that led to the discovery of 3-cyclopropylmethyl and its carboxy analogue as optimal N-3 groups are presented.
authors.affiliation: Department of Discovery Chemistry, Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. louf1203@aol.com
authors.forename: Louise H
authors.initials: LH
authors.lastname: Foley
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Pete
authors.initials: P
authors.lastname: Dunten
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Ramsey
authors.forename: Mary-Lou
authors.initials: ML
authors.lastname: Gubler
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wertheimer
mesh_terms: D018360:Crystallography, X-Ray; D006160:Guanosine Triphosphate / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C486897:1,8-dibenzylxanthine; D014970:Xanthines; D006160:Guanosine Triphosphate; D019764:Phosphoenolpyruvate Carboxykinase (ATP)