Chapter 10: The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor

First line therapy for treatment-naïve HIV patients typically include the combination of two drugs from the nucleoside or nucleotide class (N(t)RTIs), that target the viral reverse transcriptase (RT), along with either a non-nucleoside RT inhibitor (NNRTI) or HIV protease inhibitor. The N(t)RTIs therefore play an important role as the backbone of choice in HIV regimens, prompting the initiation of a research program aimed at discovering a novel, next generation N(t)RTI. The chapter describes the medicinal strategy that was used to develop a novel nucleoside phosphonate, including structure based design rationales to improve potency, resistance and selectivity. The novel NtRTI GS-9148 (22) that was discovered demonstrated a favorable resistance profile toward many clinically relevant N(t)RTI resistant isolates, and encompassed a rationally designed fluorine group to improve selectivity. To effectively deliver 22 and its active phosphorylated metabolite into lymphoid cells harboring replicating HIV, a unique prodrug strategy was employed. Prodrugs were designed as substrates of lysosomal cathepsin A, a peptidase highly expressed in lymphoid cells, to effectively target in vivo delivery of 22 to the lymphatic system. Ethylalaninyl phosphonamidate prodrug GS-9131 (32) successfully targeted 22 to peripheral blood mononuclear cells upon oral dosing in Beagle dogs (3 mg /kg) and resulted in intracellular active metabolite levels exceeding 9.0 μM, a level 5-fold higher than the HIV RT IC₅₀ of 22. The favorable preclinical profile of 32 led to its nomination as a clinical candidate for the treatment of HIV patients harboring N(t)RTI resistant virus.