787633-76-5

Upstream product

• 851664-11-4 (4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid methyl ester 
• 787633-75-4 (S)-α-(4-chlorophenyl)-α-[(R)-N-[1-(4-chlorophenyl)ethyl]-N-(cinnamoyl)amino] acetamide 
• 34837-55-3 Phenylselenyl bromide 
• 851664-13-6 (4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid 
• 27298-99-3 (R)-1-(4-chlorophenyl)ethylamine 
• 24091-92-7 methyl 2-bromo-2-(4-chlorophenyl)acetate 

Downstream Products

• 851664-19-2 5-{(S)-3-(4-Chloro-phenyl)-4-[(R)-1-(4-chloro-phenyl)-ethyl]-2,5-dioxo-7-phenyl-2,3,4,5-tetrahydro-[1,4]diazepin-1-yl}-pentanoic acid tert-butyl ester 
• 787633-77-6 (3S)-1,3-dihydro-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-phenyl-1,4-diazepine-2,5-dione 

Relevant academic research and scientific papers

Combinational therapy involving a small molecule inhibitor of the MDM2: P53 interaction

The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.

Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists

Crystallographic analysis of ligands bound to HDM2 suggested that 7-substituted 1,4-diazepine-2,5-diones could mimic the α-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1, 4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4- chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl] valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC 50 of 13 and 3.6 μM, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers.

Substituted 1,4-diazepines and uses thereof

The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R1, R2, R9, R10, Ra, Rd and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R3 is —CO2Rd, —CO2M, —OH, —NHRd, —SO2Rd, —NHCONHRd, optionally-substituted amidino or optionally-substituted guanidino; or R3—X— is hydrogen or an electron pair; R4 is oxygen or —NR9R10; R5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R6, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R6 and R7, together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with Ra.