4-Hydroxy-5,6-dihydropyrones. 2. Potent Non-Peptide Inhibitors of HIV Protease

摘要: 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) modeled in the protease utilizing similar binding mode found for previously reported 4-hydroxybenzopyran-2-ones. Our model led us pursue synthesis 6,6-disubstituted dihydropyrones with aim filling S1 and S2 thereby increasing potency parent dihydropyrone did not fill S2. Toward this end we attached various hydrophobic hydrophilic side chains at 6-position mimic natural unnatural amino acids known be effective substrates P2 P2‘. Parent (IC50 = 2100 nM) elaborated into compounds greater than 100-fold increase [18c, IC50 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid a...