Abstract
Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HIVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.
MeSH terms
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Administration, Oral
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Animals
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Anti-HIV Agents* / administration & dosage
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Anti-HIV Agents* / chemical synthesis
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Anti-HIV Agents* / chemistry
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Anti-HIV Agents* / pharmacokinetics
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Azepines* / administration & dosage
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Azepines* / chemical synthesis
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Azepines* / chemistry
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Azepines* / pharmacokinetics
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Drug Design*
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HIV Protease Inhibitors* / administration & dosage
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HIV Protease Inhibitors* / chemical synthesis
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HIV Protease Inhibitors* / chemistry
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HIV Protease Inhibitors* / pharmacokinetics
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Models, Molecular
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Pyrazoles* / administration & dosage
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Pyrazoles* / chemical synthesis
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Pyrazoles* / chemistry
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Pyrazoles* / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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(4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-1,3-bis((3-(1H-pyrazol-3-yl)phenyl)methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
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Anti-HIV Agents
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Azepines
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HIV Protease Inhibitors
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Pyrazoles