Rovafovir etalafenamide (GS-9131), a proagent of the adenosine nucleotide analogue GS-9148, is an orally active nucleoside reverse transcriptase inhibitor (NRTI). Rovafovir etalafenamide is potent and active against a variety of NRTI mutants, and shows potent anti-HIV-1 activity [1] [2].
In Vivo, Rovafovir etalafenamide (GS-9131) is given orally to male beagle dogs at 3 mg/kg, it is rapidly absorbed, generating a maximum serum drug concentration (Cmax) of 2.5 μM, and is subsequently eliminated from plasma with an apparent terminal half-life (t1/2) of less than 20 min. As determined following i.v. administration, the systemic clearance of Rovafovir etalafenamide is approximately 1.4 liters/h/kg[3].
In Vitro, Rovafovir etalafenamide (GS-9131) shows anti-HIV-1 activity in PBMCs (EC50=3.7 nM) and MT-2 cells (EC50=150 nM). Rovafovir etalafenamide is also a potent HIV-1 inhibitor in a single-cycle infection assay with primary CD4+ T lymphocytes (EC50=24 nM). Rovafovir etalafenamide inhibits different subtypes of HIV-1 (UG-92-031 subtype A, B940374 subtype B, LJM subtype B, BR-92-025 subtype C, and UG-92-024 subtype D) clinical isolates in PBMCs with EC50s ranging from 23 to 68 nM. Rovafovir etalafenamide inhibits HIV-2 isolated in MT-2 cells (CDD77618 subtype A, CDD310248 subtype A, and CDD310319 subtype B) with EC50s ranging from 39 to 650 nM[3].
References:
[1]. Mackman RL, et al. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem. 2010;18(10):3606‐3617.
[2]. Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs. 2018;23(2):149‐157.
[3]. Cihlar T, et al. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother. 2008;52(2):655‐665.
In Vivo, Rovafovir etalafenamide (GS-9131) is given orally to male beagle dogs at 3 mg/kg, it is rapidly absorbed, generating a maximum serum drug concentration (Cmax) of 2.5 μM, and is subsequently eliminated from plasma with an apparent terminal half-life (t1/2) of less than 20 min. As determined following i.v. administration, the systemic clearance of Rovafovir etalafenamide is approximately 1.4 liters/h/kg[3].
In Vitro, Rovafovir etalafenamide (GS-9131) shows anti-HIV-1 activity in PBMCs (EC50=3.7 nM) and MT-2 cells (EC50=150 nM). Rovafovir etalafenamide is also a potent HIV-1 inhibitor in a single-cycle infection assay with primary CD4+ T lymphocytes (EC50=24 nM). Rovafovir etalafenamide inhibits different subtypes of HIV-1 (UG-92-031 subtype A, B940374 subtype B, LJM subtype B, BR-92-025 subtype C, and UG-92-024 subtype D) clinical isolates in PBMCs with EC50s ranging from 23 to 68 nM. Rovafovir etalafenamide inhibits HIV-2 isolated in MT-2 cells (CDD77618 subtype A, CDD310248 subtype A, and CDD310319 subtype B) with EC50s ranging from 39 to 650 nM[3].
References:
[1]. Mackman RL, et al. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem. 2010;18(10):3606‐3617.
[2]. Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs. 2018;23(2):149‐157.
[3]. Cihlar T, et al. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother. 2008;52(2):655‐665.