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1owj

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{{STRUCTURE_1owj| PDB=1owj | SCENE= }}
{{STRUCTURE_1owj| PDB=1owj | SCENE= }}
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'''Substituted 2-Naphthamidine Inhibitors of Urokinase'''
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===Substituted 2-Naphthamidine Inhibitors of Urokinase===
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==Overview==
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The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) &lt; 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.
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(as it appears on PubMed at http://www.pubmed.gov), where 14711304 is the PubMed ID number.
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{{ABSTRACT_PUBMED_14711304}}
==Disease==
==Disease==
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[[Category: Plasminogen activation]]
[[Category: Plasminogen activation]]
[[Category: Serine protease]]
[[Category: Serine protease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 17:16:16 2008''

Revision as of 14:16, 27 July 2008

Image:1owj.png

Template:STRUCTURE 1owj

Contents

Substituted 2-Naphthamidine Inhibitors of Urokinase

Template:ABSTRACT PUBMED 14711304

Disease

Known disease associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[191840]

About this Structure

1OWJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution., Wendt MD, Rockway TW, Geyer A, McClellan W, Weitzberg M, Zhao X, Mantei R, Nienaber VL, Stewart K, Klinghofer V, Giranda VL, J Med Chem. 2004 Jan 15;47(2):303-24. PMID:14711304

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