188947-82-2

Upstream product

• 3958-57-4 1-bromomethyl-3-nitrobenzene 
• 188947-75-3 (3aS,4R,8R,8aS)-4,8-Bis-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2,2-dimethyl-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one 
• 153059-37-1 1,2:5,6-dianhydro-3,4-O-isopropylidene-L-mannitol 
• 188947-74-2 (2R,3S,4S,5R)-1,6-bis(3,4-ethylenedioxy)phenyl-2,5-diazido-3,4-O-isopropylidenehexanediol 
• 188947-73-1 (S)-2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-{(4S,5S)-5-[(S)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1-hydroxy-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-ethanol 
• 1053636-60-4 (R)-1-{(4S,5S)-5-[(R)-1-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine 
• 52287-51-1 6-bromo-1,4-benzodioxane 

Downstream Products

• 188947-83-3 (4R,5S,6S,7R)-1,3-Bis-(3-amino-benzyl)-4,7-bis-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-5,6-dihydroxy-[1,3]diazepan-2-one 

Relevant academic research and scientific papers

Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: Synthesis, structure-activity relationship, and X-ray crystal structure analysis

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with C(max) = 0.22 μg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A? of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.