Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design.
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%).
Parks
Daniel J
DJ
Johnson & Johnson Pharmaceutical Research & Development, 665 Stockton Drive, Exton, PA 19341, USA. DPARKS2@prdus.jnj.com
LaFrance
Louis V
LV
Calvo
Raul R
RR
Milkiewicz
Karen L
KL
Marugán
Juan José
JJ
Raboisson
Pierre
P
Schubert
Carsten
C
Koblish
Holly K
HK
Zhao
Shuyuan
S
Franks
Carol F
CF
Lattanze
Jennifer
J
Carver
Theodore E
TE
Cummings
Maxwell D
MD
Maguire
Diane
D
Grasberger
Bruce L
BL
Maroney
Anna C
AC
Lu
Tianbao
T
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*
D010421:Pentanoic Acids; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C468549:Bz-423