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4-hydroxy-5,6-dihydropyrones. 2. Potent non-peptide inhibitors of HIV protease.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1997 Nov 07; Vol. 40 (23), pp. 3781-92. - Publication Year :
- 1997
-
Abstract
- The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P2 and P2'. Parent dihydropyrone 1c (IC50 = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50 = 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio] -2H-pyran-2-yl)pentanoic acid and 12c, IC50 = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3- [(2-phenyl-ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1' and S2' afforded potent HIV protease inhibitor 49 [IC50 = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-dihydro-4 -hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (< 475) have one or no chiral centers and are readily synthesized.
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents pharmacology
Binding Sites
Coumarins chemical synthesis
Coumarins pharmacology
Crystallography, X-Ray
Drug Design
HIV Protease metabolism
HIV-1 enzymology
Stereoisomerism
Structure-Activity Relationship
HIV Protease Inhibitors chemical synthesis
HIV Protease Inhibitors pharmacology
Pyrones chemical synthesis
Pyrones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 40
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9371244
- Full Text :
- https://doi.org/10.1021/jm970615f