Matrix Metalloproteinase Inhibitors: A Structure−Activity Study
Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1‘ and P3‘ substituents. The results of this study...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-01, Vol.41 (2), p.199-223 |
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| container_issue | 2 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 41 |
| creator | Levy, Daniel E Lapierre, France Liang, Weisheng Ye, Wenqing Lange, Christopher W Li, Xiaoyuan Grobelny, Damian Casabonne, Marie Tyrrell, David Holme, Kevin Nadzan, Alex Galardy, Richard E |
| description | Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1‘ and P3‘ substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities. |
| doi_str_mv | 10.1021/jm970494j |
| format | Article |
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These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1‘ and P3‘ substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970494j</identifier><identifier>PMID: 9457244</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Biological and medical sciences ; Chromatography, High Pressure Liquid ; Dipeptides - chemistry ; Dipeptides - pharmacology ; Gelatinases - antagonists & inhibitors ; Immunomodulators ; Kinetics ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 8 ; Matrix Metalloproteinase 9 ; Matrix Metalloproteinase Inhibitors ; Medical sciences ; Metalloendopeptidases - antagonists & inhibitors ; Models, Chemical ; Pharmacology. Drug treatments ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-01, Vol.41 (2), p.199-223</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-212ca5c17c70c584e83785dfc1787c03d3cf2164074a41ec151cade5c2f8d0d83</citedby><cites>FETCH-LOGICAL-a445t-212ca5c17c70c584e83785dfc1787c03d3cf2164074a41ec151cade5c2f8d0d83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm970494j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970494j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2140019$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9457244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levy, Daniel E</creatorcontrib><creatorcontrib>Lapierre, France</creatorcontrib><creatorcontrib>Liang, Weisheng</creatorcontrib><creatorcontrib>Ye, Wenqing</creatorcontrib><creatorcontrib>Lange, Christopher W</creatorcontrib><creatorcontrib>Li, Xiaoyuan</creatorcontrib><creatorcontrib>Grobelny, Damian</creatorcontrib><creatorcontrib>Casabonne, Marie</creatorcontrib><creatorcontrib>Tyrrell, David</creatorcontrib><creatorcontrib>Holme, Kevin</creatorcontrib><creatorcontrib>Nadzan, Alex</creatorcontrib><creatorcontrib>Galardy, Richard E</creatorcontrib><title>Matrix Metalloproteinase Inhibitors: A Structure−Activity Study</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1‘ and P3‘ substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.</description><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Dipeptides - chemistry</subject><subject>Dipeptides - pharmacology</subject><subject>Gelatinases - antagonists & inhibitors</subject><subject>Immunomodulators</subject><subject>Kinetics</subject><subject>Matrix Metalloproteinase 2</subject><subject>Matrix Metalloproteinase 8</subject><subject>Matrix Metalloproteinase 9</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - antagonists & inhibitors</subject><subject>Models, Chemical</subject><subject>Pharmacology. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1998-01, Vol.41 (2), p.199-223 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Biological and medical sciences Chromatography, High Pressure Liquid Dipeptides - chemistry Dipeptides - pharmacology Gelatinases - antagonists & inhibitors Immunomodulators Kinetics Matrix Metalloproteinase 2 Matrix Metalloproteinase 8 Matrix Metalloproteinase 9 Matrix Metalloproteinase Inhibitors Medical sciences Metalloendopeptidases - antagonists & inhibitors Models, Chemical Pharmacology. Drug treatments Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Structure-Activity Relationship |
| title | Matrix Metalloproteinase Inhibitors: A Structure−Activity Study |
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