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    
Abstract/OtherAbstract:
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.
Authors:
S H Reich; M Melnick; M J Pino; M A Fuhry; A J Trippe; K Appelt; J F Davies; B W Wu; L Musick
Related Documents :
1443599 - An ultrasensitive human immunodeficiency virus type 1 protease radioimmuno rate assay w...
15006369 - Crucial amides for dimerization inhibitors of hiv-1 protease.
19523819 - N-(4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4h-pyrazino[1,2-a]py...
11667209 - Preparation of aminoalkyl chlorohydrin hydrochlorides: key building blocks for hydroxye...
15980379 - Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors.
20693659 - Structural studies of the catalytic core of the primate foamy virus (pfv-1) integrase.
24223749 - Structural and enzymatic characterization of the phosphotriesterase ophc2 from pseudomo...
10581549 - Open conformation of a flavocytochrome c3 fumarate reductase.
18179229 - Quantum mechanical design of enzyme active sites.
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    
Affiliation:
Agouron Pharmaceuticals, Inc, San Diego, California 92121, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
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
Humans
Models, Molecular
Structure-Activity Relationship
Chemical
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


Previous Document:  Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile rece...
Next Document:  Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative ...