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A series of hydroxyethylpiperazine HIV-1 protease inhibitors containing various monocyclic or bicyclic thienylmethyl substituents as P 3 ligands were prepared. They were found to exhibit extremely high potency in the enzyme inhibition assay. These inhibitors also proved to be highly effective against viral spread in a whole cell assay. Some representative compounds in this series have been examined for oral bioavailability in dogs and the pharmacokinetic properties were found to be somewhat related to their aqueous solubilities.