Introduction of a unique phosphonate moiety at the P1 position of the TMC-126 (3) scaffold provided a series of novel HIV-1 protease inhibitors (PIs) with an improved resistance profile against highly resistant variants. Optimization of the linker and phosphonate moieties lead to the identification of GS-8374 (1). Compound 1 is a potent and orally bioavailable HIV-1 PI with a superior resistance profile against a spectrum of patient-derived HIV-1 variants highly resistant to multiple PIs. Synthesis and characterization of 1 are reported. Because of its favorable pharmacological profile, GS-8374 (compound 1) has been further explored as a potential candidate for clinical development.