Thiophene derivatives as extremely high affinity P3′ ligands for the hydroxyethylpiperazine class of HIV-1 protease inhibitors

✍ Scribed by B. Moon Kim; James P. Guare; Joseph D. Vacca; Stuart R. Michelson; Paul L. Darke; Joan A. Zugay; Emilio A. Emini; William Schleif; Jiunn H. Lin; I.W. Chen; Kari Vastag; Paul S. Anderson; Joel R. Huff

• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 297 KB
• Volume: 5
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/0960-894x(95)00005-e

✦ Synopsis

A series of hydroxyethylpiperazine HIV-1 protease inhibitors containing various monocyclic or bicyclic thienylmethyl substituents as Py 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.

The life cycle of human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), has been intensely studied and many of its gene products have been identified. 1 Among them, HIV-1 protease (HIV PR) plays a critical role in the maturation of the viral particle. 2