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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
10
|
| pubmed:dateCreated |
1997-6-6
|
| pubmed:abstractText |
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 Cmax = 0.22 microg/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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-2623
|
| pubmed:author |
pubmed-author:BachelerL TLT,
pubmed-author:ChangC HCH,
pubmed-author:CordovaBB,
pubmed-author:CorneliusLL,
pubmed-author:Erickson-ViitanenSS,
pubmed-author:GarberSS,
pubmed-author:Gorey-FeretL JLJ,
pubmed-author:HolleyE SES,
pubmed-author:JacobsKK,
pubmed-author:JadhavP KPK,
pubmed-author:KlabeR MRM,
pubmed-author:LamG NGN,
pubmed-author:LogueK AKA,
pubmed-author:NugielD ADA,
pubmed-author:ReidCC,
pubmed-author:SeitzS PSP
|
| pubmed:issnType |
Print
|
| pubmed:day |
9
|
| pubmed:volume |
40
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1465-74
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9154969-Animals,
pubmed-meshheading:9154969-Anti-HIV Agents,
pubmed-meshheading:9154969-Biological Availability,
pubmed-meshheading:9154969-Cell Line,
pubmed-meshheading:9154969-Crystallography, X-Ray,
pubmed-meshheading:9154969-Dogs,
pubmed-meshheading:9154969-HIV Protease Inhibitors,
pubmed-meshheading:9154969-Humans,
pubmed-meshheading:9154969-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9154969-Mass Spectrometry,
pubmed-meshheading:9154969-Structure-Activity Relationship,
pubmed-meshheading:9154969-Urea
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
|
| pubmed:affiliation |
The DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
|
| pubmed:publicationType |
Journal Article
|