title: Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design.
abstract: Guided by structure-based drug design, modification of the 1,4-benzodiazepin-2,5-dione lead compound 1 resulted in the discovery of 19, a potent and orally bioavailable antagonist of the HDM2-p53 protein-protein interaction (FP IC50 = 0.7 microM, F approximately 100%).
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, 665 Stockton Drive, Exton, PA 19341, USA. DPARKS2@prdus.jnj.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Louis V
authors.initials: LV
authors.lastname: LaFrance
authors.forename: Raul R
authors.initials: RR
authors.lastname: Calvo
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Marugán
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Carol F
authors.initials: CF
authors.lastname: Franks
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Carver
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Diane
authors.initials: D
authors.lastname: Maguire
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Grasberger
authors.forename: Anna C
authors.initials: AC
authors.lastname: Maroney
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
mesh_terms: D000478:Alkylation; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000737:chemistry; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010421:Pentanoic Acids; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C468549:Bz-423