Nonpeptidal P-2 ligands for HIV protease inhibitors: Structure-based design, synthesis, and biological evaluation

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dc.contributor.authorGhosh, AKko
dc.contributor.authorKincaid, JFko
dc.contributor.authorWalters, DEko
dc.contributor.authorChen, Yko
dc.contributor.authorChaudhuri, NCko
dc.contributor.authorThompson, WJko
dc.contributor.authorCulberson, Cko
dc.contributor.authorFitzgerald, PMDko
dc.contributor.authorLee, Hee Yoonko
dc.contributor.authorMcKee, SPko
dc.contributor.authorMunson, PMko
dc.contributor.authorDuong, TTko
dc.contributor.authorDarke, PLko
dc.contributor.authorZugay, JAko
dc.contributor.authorSchleif, WAko
dc.contributor.authorAxel, MGko
dc.contributor.authorLin, Jko
dc.contributor.authorHuff, JRko
dc.date.accessioned2013-03-02T20:25:21Z-
dc.date.available2013-03-02T20:25:21Z-
dc.date.created2012-02-06-
dc.date.created2012-02-06-
dc.date.issued1996-08-
dc.identifier.citationJOURNAL OF MEDICINAL CHEMISTRY, v.39, no.17, pp.3278 - 3290-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://hdl.handle.net/10203/75376-
dc.description.abstractDesign and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S-2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.-
dc.languageEnglish-
dc.publisherAMER CHEMICAL SOC-
dc.subjectPROTEINASE-INHIBITORS-
dc.subjectCYCLIC SULFOLANES-
dc.subjectCRYSTAL-STRUCTURE-
dc.subjectRATIONAL DESIGN-
dc.subjectPOTENT-
dc.subjectTARGET-
dc.subjectAIDS-
dc.subjectP-2-LIGANDS-
dc.subjectL-735,524-
dc.subjectREAGENTS-
dc.titleNonpeptidal P-2 ligands for HIV protease inhibitors: Structure-based design, synthesis, and biological evaluation-
dc.typeArticle-
dc.identifier.wosidA1996VC70400009-
dc.identifier.scopusid2-s2.0-10144241705-
dc.type.rimsART-
dc.citation.volume39-
dc.citation.issue17-
dc.citation.beginningpage3278-
dc.citation.endingpage3290-
dc.citation.publicationnameJOURNAL OF MEDICINAL CHEMISTRY-
dc.identifier.doi10.1021/jm960128k-
dc.contributor.localauthorLee, Hee Yoon-
dc.contributor.nonIdAuthorGhosh, AK-
dc.contributor.nonIdAuthorKincaid, JF-
dc.contributor.nonIdAuthorWalters, DE-
dc.contributor.nonIdAuthorChen, Y-
dc.contributor.nonIdAuthorChaudhuri, NC-
dc.contributor.nonIdAuthorThompson, WJ-
dc.contributor.nonIdAuthorCulberson, C-
dc.contributor.nonIdAuthorFitzgerald, PMD-
dc.contributor.nonIdAuthorMcKee, SP-
dc.contributor.nonIdAuthorMunson, PM-
dc.contributor.nonIdAuthorDuong, TT-
dc.contributor.nonIdAuthorDarke, PL-
dc.contributor.nonIdAuthorZugay, JA-
dc.contributor.nonIdAuthorSchleif, WA-
dc.contributor.nonIdAuthorAxel, MG-
dc.contributor.nonIdAuthorLin, J-
dc.contributor.nonIdAuthorHuff, JR-
dc.type.journalArticleArticle-
dc.subject.keywordPlusPROTEINASE-INHIBITORS-
dc.subject.keywordPlusCYCLIC SULFOLANES-
dc.subject.keywordPlusCRYSTAL-STRUCTURE-
dc.subject.keywordPlusRATIONAL DESIGN-
dc.subject.keywordPlusPOTENT-
dc.subject.keywordPlusTARGET-
dc.subject.keywordPlusAIDS-
dc.subject.keywordPlusP-2-LIGANDS-
dc.subject.keywordPlusL-735,524-
dc.subject.keywordPlusREAGENTS-
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