Structure-based design of HIV protease inhibitors: pharmacokinetic optimization

HIV protease (HIVPR) is an attractive target for the chemotherapy of AIDS by virtue of its essential role in virus maturation. Most protease inhibitors, however, display unfavorable pharmacokinetic and pharmaceutic properties due to their high molecular weight, low aqueous solubility and rapid in vivo elimination. Iterative structure-based design and synthesis of symmetry-based HIVPR inhibitors produced agents containing achiral anthranilamide as P2/P2' ligands, which, while potent HIVPR inhibitors, exhibited poor oral bioavailability and rapid elimination. A series of lower molecular weight inhibitors with anthranilamide, benzamide or other groups as ligands was designed and synthesized using the crystal structure of inhibitor/HIVPR complexes. Inhibition constants for HIVPR were measured using a fluorogenic substrate, and inhibition of viral infection was determined in an in vitro CEM cell-based assay. In addition, pharmacokinetic studies were conducted in rats following i.v. and p.o. administration. Compounds were evaluated in terms of potency of activity, elimination half-life, and plasma levels following p.o. administration. The newly designed inhibitors typically demonstrated inhibition of HIVPR at low pM concentrations and antiviral activity at low nM concentrations. Oral bioavailabilities were generally low. One inhibitor containing anthranilamide and tetrahydrofuranyl carbamoyl ligands, despite having an oral bioavailability of only 6%, showed maximum plasma concentrations following p.o. administration above 1 micromolar, and levels well in excess of those required for antiviral efficacy after 24 hours. This study has helped to elucidate chemical structural elements associated with HIVPR inhibition, antiviral activity and pharmacokinetic behavior which will contribute to the design of inhibitors with potent activity and improved pharmacokinetic properties in an ongoing synthetic effort.

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