Biological Activity
lersivirine (uk-453061) is a next-generation non-nucleoside reverse transcriptase inhibitor (nnrti)for human immunodeficincy virus (hiv) infection with ic50 value of 119 nm [1].hiv is a retro virus that causes hiv infection and acquired immunodeficiency syndrome (aids). it may infect vital cells of human immune system such as helper t cells and dendritic cells. hiv transcriptase plays an important role in the infection process. hiv carries a reverse transcriptase which can transcript single-stranded virus rna into double-stranded dna. when the virus anchor to the target cell surface, the reverse transcriptase will be injected into host cell, there it may complete the transcription. and the transcribed dna is able to integrate into host genome to complete infection and viral replication.lersivirine (uk-453061) is a nnrti with a unique resistance profile that exhibits potent antiretroviral activity against wild-type hiv and clinically relevant nnrti-resistant strains. when lersivirine was tested with a panel of isolated wild-type and drug-resistant hiv reverse transcriptase, it exhibited excellent inhibitory activity, which confirmed the high potency of it as the next-generation anti-hiv nnrti. the compound also has good aqueous solubility and formulation characteristics which enable further in vivo evaluation [2].mated crl:cd1 mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. the first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. exposure of lersivirine did not cause any increases in external, visceral, or skeletal malformation, which demonstrated lersivirine is not teratogenic in mice [3].
References
[1] mowbray c e et al. , pyrazole nnrtis 4: selection of uk-453,061 (lersivirine) as a development candidate. bioorg med chem lett. 2009, 19(20):5857-60.
[2] davis j et al. , the effect of lersivirine, a next-generation nnrti, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects. eur j clin pharmacol. 2012, 68(11):1567-1572.
[3] cappon g d et al. , developmental toxicity study of lersivirine in mice. birth defects res b dev reprod toxicol. 2012, 95(3):225-30.
