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| [[Image:1sbg.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1sbg| PDB=1sbg | SCENE= }} | | {{STRUCTURE_1sbg| PDB=1sbg | SCENE= }} |
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| '''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS'''
| | ===AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS=== |
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| ==Overview==
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| (2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys.
| | The line below this paragraph, {{ABSTRACT_PUBMED_7918383}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 7918383 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_7918383}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Abdel-Meguid, S.]] | | [[Category: Abdel-Meguid, S.]] |
| [[Category: Zhao, B.]] | | [[Category: Zhao, B.]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:30:42 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:46:28 2008'' |
