Document Detail

Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: secondary amide series.
MedLine Citation:
PMID:  8709109     Owner:  NLM     Status:  MEDLINE    
The design, synthesis, and crystallographic analysis of protein-inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr)inhibitors. Beginning with a cocrystal structure of a Phe-Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (Ki = 24.5 microM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, Ki = 0.48 microM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.
S H Reich; M Melnick; M J Pino; M A Fuhry; A J Trippe; K Appelt; J F Davies; B W Wu; L Musick
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  39     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1996 Jul 
Date Detail:
Created Date:  1996-09-10     Completed Date:  1996-09-10     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2781-94     Citation Subset:  IM; X    
Agouron Pharmaceuticals, Inc, San Diego, California 92121, USA.
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MeSH Terms
Amides / chemistry*,  pharmacology
Antiviral Agents / chemistry*,  pharmacology
Butanols / chemistry,  pharmacology*
Cell Line
Crystallography, X-Ray
Drug Design
HIV Protease Inhibitors / chemistry*,  pharmacology
HIV-1 / drug effects*,  enzymology
Models, Molecular
Structure-Activity Relationship
Reg. No./Substance:
0/Amides; 0/Antiviral Agents; 0/Butanols; 0/HIV Protease Inhibitors; 78-92-2/2-butanol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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